US 2006.0035981A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0035981 A1 Mazzio et al. (43) Pub. Date: Feb. 16, 2006
(54) INHIBITION OF ANAEROBIC GLUCOSE Publication Classification METABOLISMAND CORRESPONDING COMPOSITIONAS ANATURAL NON-TOXC (51) Int. Cl. APPROACH TO CANCERTREATMENT A61 K 3L/I 2 (2006.01) A61K 31/7072 (2006.01) A61K 31/7076 (2006.01) A6IK 3I/525 (2006.01) (76) Inventors: Elizabeth Anne Mazzio, Tallahassee, A6IK 36/328 (2006.01) FL (US); Karam F. Soliman, A6IK 36/23 (2006.01) Tallahassee, FL (US) A61K 36/906 (2006.01) (52) U.S. Cl...... 514/690; 514/45; 514/51; Correspondence Address: 514/27; 514/251; 424/725; Karam Soliman 424/748; 424/756; 424/745; Florida A& M University 424/746; 424/729 College of Pharmacy and Pharmaceutical (57) ABSTRACT Sciences This invention discloses a method and formulation for 104. Dyson Building treatment/prevention of human and animal cancers. The Tallahassee, FL 32307 (US) invention is designed to exploit the Vulnerability of cancer with regards to its anaerobic requirement for non-oxidative phosphorylation of glucose to derive energy, which is oppo (21) Appl. No.: 11/233,279 Site to the host. The composition is comprised of a combi nation of one or more of (A) 2,3-dimethoxy-5-methyl-1,4- benzoquinone, ubiquinones (5-45) (B) compound(s) capable (22) Filed: Sep. 20, 2005 of augmenting oxidative phosphorylation Such as a ribofla Vin containing compound and/or ubiquinone (50) (C) 2.3, 4'5,7-pentahydroxyflavone or a lactic acid dehydrogenase Related U.S. Application Data inhibitor and (D) compounds (S) that antagonize gluconeo genesis from non-glucose carbon based Substrates. The (63) Continuation-in-part of application No. 10/909,590, combination of these Substances should favor oxidative loSS filed on Aug. 2, 2004, now abandoned. of carbon through decarboxylation reactions, Suppress glu coneogenesis and initiate collapse of glycolysis in tumor tissue, a chemical manipulation that should be non-toxic or (60) Provisional application No. 60/491,841, filed on Aug. perhaps even beneficial to normal respiring host tissue. Pilot 2, 2003. Provisional application No. 60/540,525, filed studies indicate the treatment to be effective without side on Jan. 29, 2004. effects. Patent Application Publication Feb. 16, 2006 Sheet 1 of 4 US 2006/0035981 A1
Effects of Oxidative Metabolism on Anaerobic Glucose Utilization in Deviant Neuroblastoma Controlled Environment Controlled Environmental Of CO2 Ratio h Of CO2 Ratio Or MPP-- Riboflavin/ FAD/FMN O2 consumption thru AO, consumption (-) Complex I thru & (+) Complex I (-) Complex IV
A. Anaerobic Metabolism "Anaerobic Metabolism v Aerobic Metabolism A. Aerobic Metabolism
Glucose Utilization Glucose Utilization Depletion in a glucose limited environment leading to starvation
CELLDEATH Figure 1 - Mazzio and Soliman, Biochem Pharmacol. Patent Application Publication Feb. 16, 2006 Sheet 2 of 4 US 2006/0035981 A1
FIGURE 2A 1000 900 Rosemary 2,3,4'5,7-pentahydroxyflavone Myrrh K - - - - - Clove 800 Green Tea - - - - Green Tea 700 Black Walt --0. --Rosemary -x-Morin 600 - Myrrh -- Black Walnut 500 400 300 200 100
0 0.5 2.5 5 O. O.3 5 3 Extract (mg/ml) Chemical (mM)
FIGURE 2B
1000 - 0 - LDH Control 900
800 - Rosemary (2.5mg/ml)
700 s Green Tea (2.5mg/ml) (*) 600
A 6is 500 -O-Morin (1.5mM) S is 400 -- Clove (2.5mg/ml) (*) a 300 Z. 200 --MyrrhM (2.5mg/ml)
100 -a-Blackwalnut (2.5mg/ml)
1 5 7 9 11 13 15 17 9 Time (Minutes) Patent Application Publication Feb. 16, 2006 Sheet 3 of 4 US 2006/0035981 A1
FIGURE 3A 100 90 80 70 60 50 40
30 f 20 - H3-bromopyruvate 10 ; --0 - 2,3-DMBQ
O 50 100 250 500 Drugs (uM)
FIGURE 3B
100%
81
40%
20%
O46
Drugs (uM) Patent Application Publication Feb. 16, 2006 Sheet 4 of 4 US 2006/0035981 A1
FIGURE 4A 6000
5000
4000
3000
2000
1 OOO
9 12 16 19 23 26 30 33 37 40 44 47 50 54 57 61 65 Days
FIGURE 4B 24.0 23.5 23.0 22.5 22.0 Control
21.5 21.0 20.5 20.0 19.5 19.0 9 12 16 19 23 26 30 33 37 40 44 47 50 54 57 61 Days US 2006/0035981 A1 Feb. 16, 2006
INHIBITION OF ANAEROBC GLUCOSE 0005 For decades, it has been widely known that the METABOLISMAND CORRESPONDING etiological pathogenesis of cancer involves an inherent but COMPOSITIONAS ANATURAL NON-TOXC unclear abnormality of glucose metabolism, one that is APPROACH TO CANCERTREATMENT divergent from typical oxidative metabolic processes of eukaryotic cells. The “Warburg effect” is a common termi CROSS-REFERENCE TO RELATED nology used to describe the observed high glycolytic activity APPLICATIONS that occurs in cancer cells, even in the presence of low oxygen (“O”) concentration. Otto Warburg was a pioneer in 0001. This application is a continuation in part of appli demonstrating that cancer cells exhibit merged basal fea cation No. U.S. Pat. No. 0,527.403 filed on Aug. 5, 2005 and tures having high capacity anaerobic and aerobic metabolic application Ser. No. 10/909,590 filed on Aug. 2, 2004, which pathways. Since then, Subsequent Studies have consistently claims the benefit under 35 USC 119(e), of previous appli corroborated the inherent nature of cancer to involve a) rapid cation(s) No. 60/491,841 filed on Aug. 2, 2003 and No. consumption of glucose b) robust glycolytic activity (Mau 60/540,525 filed on Jan. 29, 2004, all of which are herein blant et al., Bull Cancer, 85:935-50, 1998), c) rapid cell incorporated by reference. proliferation (Chesney et. al., Proc Natl Acad Sci USA, 96:3047-52, 1999), d) production and accumulation of lactic STATEMENT REGARDING FEDERALLY acid (Baggetto, Biochimie, 74:959-74, 1992) and e) a low SPONSORED RESEARCH AND extracellular pH with depleted glucose levels circumscribing DEVELOPMENT the perimeter of the tumor. Our baseline findings are con 0002 The U.S. government has certain rights to this Sistent with these experimental observations (Mazzio et al., invention as federal support was provided for by NIH Grant Brain Res. 2004 Apr. 9; 1004(1-2):29-44) indicating that the NCRR O3O2O. predominant Source of energy in the form of ATP is being produced primarily through anaerobic Substrate level phos FIELD OF THE INVENTION phorylation in the cytoplasm, even in the presence of what we found to be functional mitochondria. Further, evidence 0003. The present invention describes a composition and that Suggests carbon dioxide (“CO”) can contribute to the method for treatment and/or prevention of human and ani acidity of a tumor (Helmlinger et al., Clin Cancer Res., mal cancers. The invention describes the use of compounds 8:1284-91, 2002; Griffiths et al., Novartis Found. Symp., that increase oxygen utilization and impair anaerobic 240:46-62; 62-7,152-3, 2001), and O. deprivation/tissue metabolism of cancer cells, an event that corresponds to hypoxia exacerbates the growth of cancer and resistance to Selective cancer cell death. The invention therefore, relates chemotherapy (Brizel et al., Int. J. Radiat. Oncol. Biol. to the fields of pharmacology, oncology, medicine, medici Phys., 51:349-53, 2001; Brizel et al, Int. J. Radiat. Oncol. nal chemistry and biochemistry. Biol. Phys., 38:285-290, 1997; Alagoz et al., Cancer 75:2313-22, 1995), both clearly indicate that cancer has a DESCRIPTION OF THE RELATED ART preference for CO and a low requirement/preference for lack of O. We conjecture that if the low requirement for O. 0004 Current chemotherapy for cancer often employs involves a non-requirement for mitochondrial oxidative the use of drugs that are generally toxic to the body as well phosphorylation (OXPHOS) to derive energy from glucose, as the tumor. The efficacy of drugs are often in close proximity to Systemic toxic effects, rendering a narrow this vulnerability could possibly be exploited in order to kill therapeutic index. It is the objective of this invention to the cancer without harm to the body. widen that gap by recognizing and exploiting a major 0006 Basically, our initial studies in vitro, demonstrate difference between the host and the tumor with regards to that cancer cells a) readily survive without Ob) prefer CO how each derives energy (adenosine-5'-triphosphate (ATP)) and c) that changes in O/CO are intricately involved with from glucose. This invention delineates a natural formula the way in which cancer cells metabolize glucose which tion that should strategically Starve the tumor by blocking Subsequently control either cell death or cell viability/ anaerobic utility of glucose, while Specifically augmenting proliferation. Moreover, experimental block of mitochon aerobic energy metabolism of the host. The combined events drial respiratory function (e.g. with use of mitochondrial should render non-toxic effects on the host and a detrimental monocarboxylic pyruvate transport blocker, toxins Such as adverse effect specific to the tumor. We initiated a diverse 1-methyl-4-phenylpyridinium (MPP+), rotenone), the range of Studies in order to elucidate the aberrant nature of absence of O or a high concentration of CO2, are all glucose metabolism within malignant blastoma in vitro, and conditions that can prompt a robust potentiation of glucose Subsequently formulated a test composition which was metabolism through glycolysis, while having no toxic found effective in arresting MD-MB-231 human mammary effects other than depletion of glucose Supply in a glucose carcinoma in a Xenograft model using Nu/Nu nude mice, limited environment (Mazzio and Soliman, Biochem Phar comparable to paclitaxel (taxolf) in a pilot study. The pilot macol. 67:1167-84, 2004, Brizel et al., Int. J. Radiat. Oncol. formulation did not appear to have any adverse effect on the Biol. Phys., 51:349-53, 2001; Brizel et al., Int. J. Radiat. animal's health as evident by absence of change in behavior, Oncol. Biol. Phys., 38:285-290, 1997). These findings sug appetite, weight loSS, food intake or excretory function. gest cancer cells are completely anaerobic in nature, while Moreover, the treatment was also effective in its water having expendable oxidative apparatus. In contrast, we Soluble form and may be altered to Suit a range of Solubili found that an increase in the concentration of O, a drop in ties, thereby eliminating requirements for emulsifying the CO/O ratio, or potentiating the function of the mito agents or Solvent vehicles that can at times lead to compli chondria all render collapse of Substrate level phosphoryla cation associated with chemotherapy Such as hyperSensitiv tion (anaerobic ATP production from glucose) in cancer ity reactions. cells, an event that corresponds to cell death. These results US 2006/0035981 A1 Feb. 16, 2006
indicate that tumor cells are not only anaerobic in nature, but a critical role in directing aggressive malignancies (Walenta react adversely to Substrates or Substances that augment and Mueller-Klieser. Semin Radiat Oncol2004; 14:267-74), aerobic mitochondrial function. And, there is an inverse and its enzyme function is required to generate NAD+ as an opposing force between anaerobic and aerobic Systems enzymatic product and cofactor for glyceraldehyde 3-phos within the same cell. Further, these findings Suggest that phate dehydrogenase which propels ATP production through glucose metabolism in cancer is in direct opposition to the phosphoglycerate/pyruvate kinase. Interestingly, while it host, which favors aerobic conditions, where enhanced may seem implausible that direct LDH inhibition would not mitochondrial function is beneficial, mitochondrial toxins render the body harm, we have Screened a number of are poisonous and a high concentration of CO can lead to compounds and Our research Suggests that the most powerful Suffocation through the halt of mitochondrial energy pro anti-cancer flavonoids commonly consumed and Sold over duction. This metabolic anomaly we found to be consistent the counter, also inhibit the activity of LDH (LDH-5 (M)) amongst cancer cells of various origin Such as human, rat (not yet published), an enzyme most resembling that inher and mouse. ent to human cancer (Koukourakis et al., Br J Cancer. 2003; 0007 From this, we conjectured that if O (a substrate for 89:877-85; Augoff and Grabowski. Pol Merkuriusz Lek complex IV of the electron transport chain) is toxic to cancer 2004; 17:644-7; Nagai et al., Int J Cancer. 198815;:10-6; cells, where the loss of complex IV function (via MPP+) is Evans et al., Biol. Chem. 1985; 260:306-14). Yet, this has beneficial to cancer cells in terms of metabolic activation not yet been investigated as a likely avenue by which plant and glucose metabolism, then would it Suffice to Say that derived compounds exert well known anti-cancer effects other mitochondrial Substrates that Serve to augment respi (Rosenberg et al., J. Chromatogr B Analyt Technol Biomed ratory function be detrimental to glucose metabolism within Life Sci. 777: 219–32, 2002; Stoner and Mukhtar, J Cell cancer cells? And, if this event is further combined with Biochem Suppl. 22:169-80, 1995). Prior research defining direct Selective inhibition of lactic acid dehydrogenase tumoricidal effects of flavonoids have focused on cell Sig enzyme activity (LDH), could this block glucose utilization naling, inhibition of protein kinase, tyrosine kinase, cyclin Specifically in cancer cells? The combined manipulation dependent kinases, cell cycle phases G0/G1 or G2/M, pro should, in theory, yield greater concentration of pyruvate to liferation or induction of apoptosis (Faderland Estrov, Leuk fuel aerobic oxidative function by blocking its ability to Res. 27, 471-3, 2003;. Agullo et al., Biochem Pharmacol. drive substrate level phosphorylation through LDH. In brief 53:1649-57, 1997). Our results indicate that specific fla Summary, our findings demonstrate that a kinetic potentia vonoids can directly inhibit LDH possibly by oxidation of tion of the V and reduction of K of mitochondrial thiol group function, thereby impairing the catalytic region complex I can yield a robust enhancement of O. utilization of the enzyme. And, if this is so, the loss of ATP through through cytochrome oxidase (complex IV) in cancer cells. substrate level phosphorylation as a result of LDH inhibition This event alone, is analogous to high O concentration, and would render a cavalcade of the observed down stream creates a significant Vulnerability by impairing the use of apoptotic events. The importance of LDH itself, in the glucose to produce ATP through Substrate level phosphory progression of cancer has been Substantiated, albeit rela lation (Mazzio and Soliman, Biochem Pharmacol. 67:1167– tively sparsely considering the magnitude of its role, in the 84, 2004). If anaerobic metabolism is further blunted by literature (Shim et al., Proc Natl AcadSci USA. 94:6658-63. downregulation/inhibition of cytosolic LDH, a block of 1997; Sun et al., Zhonghua Zhong Liu Za Zhi 13:433-5, anaerobic glucose utilization occurs, corresponding to Selec 1992). The downregulation of LDH in BGC-823 gastric tive tumor cell death through loss of energy production (not carcinoma cells can induce tumoricidal effects (Yang et. al., yet published). Lastly, our research also Suggests a compo Zhonghua Zhong Liu Za Zhi 18:10-2, 1996) and remission nent of anaerobic glucose metabolism in cancer cells-that of cancer and Survival rates in humans undergoing chemo includes a robust capacity for gluconeogenesis from non therapy to platinum drugs corresponds to a diagnostic reduc glucose carbon based Substrates and variants of carboxyla tion in serum LDH (Velasquez et al., Blood 71:117-22, tion reactions, with potential roles for the following 1998). Interestingly, while studies demonstrate heightened enzymes: acetate-coA ligase, malate Synthase, isocitrate LDH concentrations to be associated with aggressive malig lyase, aconitase, phosphoenolpyruvate carboxylase/carbox nancies, the use, synthesis or evaluation of LDH inhibitors ykinase, glycolate oxidase, phosphoglycolate phosphatase, to actually treat cancer have not yet been described in the glycolaldehyde dehydrogenase, pyruvate carboxylase, cit research literature. Further, our findings Suggest that LDH rate lyase, ferridoxin oxidoreductase, fructose 1,6-bisphoS inhibition could be lethal to cancer, but not as detrimental to phatase, 2,3-diphosphoglycerate mutase, propionyl CoA car the host as one would be inclined to think. In this invention, boxylase, malic enzyme, acetyl CoA carboxylase and LDH inhibition is a part of the optimal synergistic combi ribulose-1,5-bisphosphate carboxylase, even though Some of nation of chemicals that should signal collapse of anaerobic these are not known to be inherent to tumor tissue. The glycolysis in cancer cells while having potentially beneficial invention is a composition and means to specifically block effects on aerobic metabolic activity of the host. glucose metabolism in cancer cells by combining agents that 0009 While the descriptive embodiment defines a new 1) inhibit LDH (without affecting glycolysis) 2) inhibit Slant on the approach to treatment, with regards to the use of anapleurotic gluconeogenic pathways and 3) optimize aero Specific compounds to alter oxidative glucose metabolism bic metabolism by potentiating mitochondrial function. through enzymatic modulation, the concept is in alignment 0008 While there has been relatively little to no research with existing Scientific findings. While the mechanism is not investigating the optimization of mitochondrial function or known as to why O is toxic to cancer cells, Studies are inhibition of anapleurotic gluconeogenic pathways to down generally consistent in reporting a deprivation of Oz (ie regulate the growth of cancer, the block of ATP production hypoxia) to be associated with potentiation of glycolysis through substrate level phosphorylation by inhibition of (Nielsen et al., Cancer Res.61:5318-25, 2001) and enhanced LDH in hindsite appears to be an obvious target. LDH plays tumor proliferation (Brizel et al., Int. J. Radiat. Oncol. Biol. US 2006/0035981 A1 Feb. 16, 2006
Phys., 38:285 290, 1997). Similarly, improved therapeutic the potential use for short chain ubiquinones. Of the few efficacy has been observed using carbogen (95% O/5% publications noted, CoQ0 has been described in an oral CO2) to augment radiotherapeutic response to transplanted hygiene formulation owned by SmithKline (WO03037284, rat GH3 prolactinomas (Robinson et al., Br J. Cancer, 82: May 08, 2003, Hynes) and the use of coenzyme Q2, Q4, Q6 2007-14, 2000), and hyperbaric O arrests the growth of in a method for treating or preventing mitochondrial dyS tumors resistant to chemotherapy and potentiates the effects function associated with Friedreich Ataxia, hypertrophic of cisplatin (Alagoz et al., Cancer 75:2313-22, 1995). While cardiomyopathy, Hallervorden-Spatz disease and sidero the previous research Suggests a physical approach to capi blastic anemia (U.S. Pat. No. 6,133,322, Oct. 17, 2000, talize on the difference between the host and cancer regard Rustin and Roetig). Coenzyme Q2 has been used as a ing concentration and Supply of Oz, the embodied invention component in a formulated treatment for dementia is by nature chemical, and achieves the same means by (JP4112823, Apr. 14, 1992, Imagawa) and Q9 has been increasing the aerobic (O2 requiring)/anaerobic glucose described in combination with CoQ10 for poultry feed metabolic ratio. A pilot test composition was formulated in formulations (EP0913095, May 6, 1999, Aoyama and Sug order to contain agents that could optimize aerobic mito imoto). There is also meager technical research investigating chondrial function and promote greater yield of pyruvate efficacy or use for DMBQ, other than a few studies that toward the mitochondria, while Suppressing anaerobic glu define it as protective effects against lipid peroxidation in cose utility and the ability of pyruvate to Sustain Substrate kidney, liver, heart, lung and Spleen tissue in animal models level phosphorylation through LDH (without affecting the of oxidative injury (Knudsen et al., Free Radic Biol Med. remainder of the glycolytic pathway), an otherwise critical 1996; 20(2):165-73; Chen and Tappel, Free Radic Biol Med. requirement for tumor cells to utilize glucose to produce 1995 May; 18(5):949-53). On the other hand, structurally ATP. The treatment was found to be effective in arresting related derivatives of CoQ (e.g. chloroquinones and alkylm MD-MB-231 human mammary carcinoma in a xenograft ercapto-1,4-benzoquinones) (Porter et al., Bioorganic model using Nu/Nu nude mice comparable to taxolf), while Chemistry 1978: 7:333-350; Folkers et al., Res Comm Chem having no adverse effects on the animals with regards to Path Pharm 1978: 19(3) 485-490; Wikholm et al., Journal of health, behavior, appetite or weight loss. Although prelimi Med Chem 1974:17:893-896) and a range of structurally nary, this Suggests that the embodiments of the present Similar compounds (e.g. 2,5-diaziridinyl-3,6-bis (carboet invention may yield significant tumor Suppression without hoxyamino)-14 benzoquionone (U.S. Pat. No. 4,233,215, toxicity to the host. Similarly, Studies employing the use of Nov. 11, 1990, Driscollet al.) and 6-methoxy-10-cis-hep individual chemicals that comprise this invention in non tadecene-1,4-benzoquinone (CN 1362061, Aug. 7, 2002, analogous Studies, do not report toxicity, death or adverse Dehua et al.) have been described as anti-tumor agents. effects on animal models when administered up to 300 0012. On the other hand, there is abundant literature on mg/kg (Knudsen et al., Free Radic Biol Med CoQ1 which is widely known for its role as a cofactor in 1996:20(2):165-73; Chen et al., Free Radic Biol Med mitochondrial enzymes that carry out oxidation-reduction 1995:20(5):949-953). The chemicals and substances that reactions involved with aerobic ATP production. Our studies mediate effects through the described mechanism and that Suggest that CoQ10 can increase the V of mitochondrial comprise the formulation, can be purchased from chemical complex II activity in cancer cells (Mazzio and Soliman, distributors and/or can be Synthesized or extracted from Biochem Pharmacol. 67:1167-84, 2004) however, this did natural Substances, as described below. not control the rate of mitochondrial respiration or O. 0.010 Briefly, the formulation contains one or more com utilization through complex IV. And, we did not find CoQ10 pounds that Synergistically promote oxidative metabolism to be as lethal as expected. Likewise, previous Studies that and/or impede lactic acid dehydrogenase or anaerobic glu have employed CoQ10 against cancer have been Somewhat cose metabolism. The formulation can contain 2,3- contradictory. For example, Several reports show a positive dimethoxy-5-methyl-1,4-benzoquinone (herein also termed inverse correlation where low physiological Q10 concentra “DMBQ") (quinoid base), and options for the entire tions are associated with greater risk for cancer (Palan P R ubiquinone Series including corresponding hydroquinones, et al., Eur JCancer Prev. 2003 August; 12(4):321-6; Portakal ubichromenols, ubichromanols or Synthesized/natural et al., Clin Biochem. 2000 June; 33(4):279-84; Jolliet Pet derivatives and analogues. Ubiquinone structures are desig al., IntJ Clin Pharmacol Ther. 1998 September; 36(9):506 nated by the number of isoprene units attached to the 9) and its administration induces tumoricial effects (Gorelick 2,3-dimethoxy-5-methyl-1,4-benzoquinone base, which C et al., Am J ObstetGynecol. 2004 May; 190(5):1432-4), designates the term “coenzyme Qn'. Ubiquinones are also blocks the growth of cancer (Lockwood Ket al., Biochem defined as the number of carbon atoms comprising the side Biophys Res Commun. 1995 Jul. 6; 212(1): 172-7; Lock chain and termed "ubiquinone (x)' where X is (0-50+ carbon wood et al., Biochem Biophys Res Commun; 1994 Mar. 30; atoms) and each isoprenene unit constitutes a 5 carbon atom 199(3)1504-1508; Folkers et al., Biochem Biophys Res extension. Commun 1993 Apr. 15; 192(1) 241-245) and reduces side 0.011 The embodiment of the invention establishes the effects of chemotherapy (Roffe Let al., J. Clin Oncol. 2004 Short chain ubiquinones (CoQ-3) as anti-cancer agents. Nov. 1; 22(21):4418-24; Perumal S S et al., Chem Biol More specifically, 2,3-dimethoxy-5-methyl-1,4-benzo Interact. 2005 Feb. 28; 152(1):49-58). The positive results quinone (DMBQ) is in excess of 1000x more potent than are not always reported (Roffe et al., Journal of Clin Oncol CoQ10 as an anti-cancer agent, causing collapse of anaero ogy 2004; 22(21) 4418-4424; Prieme H et al., Am J Clin bic glucose metabolism through a mechanism we are con Nutr. 1997 February; 65(2):503-7; Hodges et al., Biofactors tinuing to explore, possibly involving enzymes integral for 1999; 9(2-4):365-70; Lesperance et al., Breast Cancer Res gluconeogensis in converting non-glucose carbon based Treat. 2002 November; 76(2):137-43) and the use of HMG substrates into glucose. While there is a wealth of informa CoA inhibitors which lower endogenous production of cho tion describing the use of CoQ10, there is little known about lesterol and CoQ10 do not appear to be a pre-determinant to US 2006/0035981 A1 Feb. 16, 2006 cancer (Sacks et al., Reply letters to the editor JACC 1999 very opposite fashion to the effect of mitochondrial toxins 33 (3): 897-898). On the other hand, CoQ10 has generally such as MPP+ (also targeting complex I and IV), which been used for a broad Spectrum of other disorders, Such as accelerate anaerobic glucose utilization and create an opti end-stage heart failure (Berman Met al., Clin Cardiol. 2004 mal metabolic state (Mazzio and Soliman, Brain Res. 2003 May; 27(5):295-9; Erman A, Ben-GalT, Dvir D, Georghiou Feb. 7, 962(1-2):48-60). These findings suggest that ribo GP, Stamler A, Vered Y, Vidne BA, Aravot D), chronic heart flavin could contribute toward the forcing of aerobic oxida failure (Mortensen S A Biofactors. 2003; 18(1-4):79-89), tive metabolism, and play a role in Suppressing tumor hypertension, hyperlipidemia, coronary artery disease growth. Interestingly, to this day, the role for riboflavin and (Sarter B. J. Cardiovasc Nurs. 2002 July; 16(4):9-20), heart cancer remains ambiguous and unclear. A number of earlier complications associated with use of Statin drugs (Langsjoen Studies consistently corroborated that a riboflavin deficiency PH and Langsjoen A M. Biofactors. 2003; 18(1-4): 101-11; or the use of riboflavin antagonists (eg. diethyl riboflavin) Chapidze G et al., Georgian Med News. 2005 January; had anti-tumor effects, where dietary riboflavin Supplemen (1):20-5), hypertriglyceridemia (Cicero A F et al., Biofac tation resulted in the acceleration of tumor growth and tors. 2005; 23(1): 7-14), chronic fatigue (Bentler S E et al., metastasis (Nutr Rev. 1974 October; 32(10):308-10; Shapiro J Clin Psychiatry. 2005 May; 66(5):625-32), alzheimer's and et al., Cancer Res. 1956 August; 16(7):575-80). However, parkinson's disease (Ono K et al., Biochem Biophys Res these findings were not always consistent and riboflavin was Commun. 2005 Apr. 29; 330(1):111-6; Beal M. F. J. Bioenerg consistently found to be protective against carcinogenesis by Biomembr. 2004 August; 36(4):381-6), oxidative neurode azo compounds (Rivlin, Cancer Res. 1973 September; generative injury (Somayajulu Met al., Neurobiol Dis. 2005 33(9): 1977-86). In contrast, others suggest that a deficiency April; 18(3):618-27), migraine headaches (Sandor PS et al., in riboflavin may be a risk factor for the development of Neurology. 2005 Feb. 22; 64(4):713-5), age-related loss of cervical dysplasia and various other types of cancer, where cognitive function (McDonald S R et al., Free Radic Biol high intake of riboflavin is protective against a variety of Med. 2005 Mar. 15; 38(6):729-36), muscle and cardiomyo cancers in both animals and humans (Thurnham et al., Nutr pathies (Lalani S R et al., Arch Neurol. 2005 February; Cancer. 1985; 7(3):131-43; Chen et al., Nutr Cancer. 2002; 62(2):317-20), hyperthyroidism (Menke Tet al., Horm Res. 42(1):33-40; Powers H J, Am J Clin Nutr. 2003 June; 2004; 61(4): 153-8), preeclampsia (Teran E et al., Free Radic 77(6):1352-60; Petridou, Nutr Cancer. 2002; 44(1):16-22; Biol Med. 2003 Dec. 1; 35(11): 1453-6) and cerebellar ataxia La Vecchia et al., IntJ Cancer. 1997 Nov. 14; 73(4):525-30; (Lamperti C et al., Neurology. 2003 Apr. 8; 60(7):1206-8). Key, Proc Nutr Soc. 1994 November; 53(3):605-14.). Our 0013 CoQ10 has also been incorporated into a range of findings Suggest its protective role may also be through its patented formulations Such as those known to treat cancer unique ability to propel oxidative respiratory function in (WO 02/078727, Feb. 24, 2004, Van De Wiel), endothelial cancer cells. dysfunction (CN1471390, Jan. 28, 2004, Watts and Play 0.015 The use of riboflavin has been described in few ford), skin (US2005036976, Feb. 7, 2005, Rubin and Patel), patent publications regarding cancer. Of these, its use has cardiovascular and weight gain (US2004028668, Feb. 12, been illustrated for the reduction of toxic effects of chemo 2004, Gaetani), arteriosclerosis (US2004248992, Dec. 9, therapy (WO03/045372, Jun. 5, 2003, Burzynski and Kam 2004, Fujii et al.) periodontosis (U.S. Pat. No. 6.814,958, merer), in combination with lumichrome derivative for Nov. 9, 2004, Sekimoto), post-surgical ophthalmologic suppression of tumors (JP6279445, Oct. 4, 1994, TSuzaki), pathologies (U.S. Pat. No. 6,787,572, Sep. 7, 2004, Bran as an enrichment with Vitamin E, to chinese medicines cato, et al.), neurodegenerative disease, memory loss (U.S. Scorpion, Fructus lycii, Radix glycyrrhizae, Fructus Zizyphi Pat. No. 6,733,797, May 11, 2004, Summers), mitochondrial jujubae, Rhizoma Smilacis glabrae, and FloS chrysanthemi disorders (CA2285490, Apr. 7, 2001, Sole and Jeejeebhoy), and crop liqour for treatment of cancer and Senility diabetes (CA2476906, Sep. 25, 2003, Fujii et al.) and as a (CN1081467, Feb. 2, 1994, Belin) and as a component to part of formulations that comprise antioxidants anti-cancer foods with nicotinic acid and amino acids (CA2457762, Apr. 10, 2003, De Simone), hair or scalp (JP58170463, Oct. 7, 1983, Asoujima). Moreover, riboflavin treatment (CA2444282, Dec. 19, 2002, Kawabe), Sunscreen and its derivatives have been described in patent publica (CH693624, Nov. 28, 2003, Gecomwert) and food supple tions for a wide variety of other maladies including toxic ments (U.S. Pat. No. 6,642,277, Nov. 4, 2003, Howard et shock (WO 97/36594, Mar. 28, 1997, Araki et al.), infec al.). tions, septic shock (WO 02/074313, Mar. 19, 2003, Araki et 0014) DMBQ/and ubiquinone(s) (0-45)-tubiquinone (50) al.), headache (WO 02/11731, Jul. 20, 2001, Valletta and can be combined with vitamin B2 (riboflavin: 7,8-dimethyl Banchetti), high cholesterol (WO 02/34261, Oct. 21, 2001, 10-ribityl-isoalloxazine), its derivatives and pharmaceuti Ohsawa et al.) weight loss (WO 02/060278, Jun. 13, 2001, cally acceptable Salts. Vitamin B2 is a precursor to flavin Gaetani and Cavattoni), acne (U.S. Pat. No. 6.558,656, Jun. mononucleotide (FMN) and flavin adenine dinucleotide 6, 2003, Mann), diseases of genital and mucous membranes (FAD), both which play a critical role in the oxidative (U.S. Pat. No. 6,020,333, Feb. 1, 2000, Berque), viral metabolism of glucose and fatty acids. Our results indicate infections (CA2174552, Apr. 27, 1995, Washington et al.), that unlike glucose or niacin (which propel anaerobic gly macular degeneration (U.S. Pat. No. 5,075,116, Dec. 24, colysis in cancer cells), riboflavin, FMN and FAD can 1991, LaHaye), immune disorders (WO 03/084545, Apr. 9, augment mitochondrial complex I enzyme function (over 2003, Araki et al.), hemorrhoids (CA 1147656, Jun. 7, 1983, 1000x fold increase) and exert pre-eminent control in caus Breskman), and as a part of nutritional Supplement formu ing a robust acceleration of mitochondrial cell respiration lations as one of the B-complex vitamins (U.S. Pat. No. (O, utilization) in cancer cells (Mazzio and Soliman, Bio 6,245,360, Jun. 12, 2001, Markowitz). chem Pharmacol. 67.1167-84, 2004). The effects of ribofla 0016. The formulation at most should simultaneously Vins on complex I and IV, adversely impede anaerobic augment mitochondrial oxidative respiration and inhibit (Substrate level phosphorylation) glucose utilization in the LDH. LDH inhibition should be specifically targeted, where US 2006/0035981 A1 Feb. 16, 2006
the remainder of the glycolytic pathway to the production of Offord E A, Harris C C, Pfeifer AM. Arch Toxicol Suppl. pyruvate remains unaffected. The reason for this is that the 1998; 20:227-36) and against colon cancer in vivo (Moran glycolytic pathway converts 1 mole of glucose to 2 moles of AE, Carothers AM, Weyant MJ, Redston M, Bertagnoli M pyruvate, which then can diverge to fuel either anaerobic M. Cancer Res. 2005 Feb. 1; 65(3):1097-104). The extract metabolism through LDH or it is transported to the mito of rosemary can increase the Sensitivity and prevent the chondria where it is converted to acetyl-CoA by pyruvate efflux of chemotherapeutic agents in drug resistant MCF-7 dehydrogenase to Sustain aerobic (oxidative) metabolism. The latter metabolic pathway leads to the ultimate genera human breast cancer cells (Plouzek CA, Ciolino HP, Clarke tion of reducing equivalents (NADH2/FADH2) by clock R, Yeh G C., Eur J Cancer. 1999 October; 35(10): 1541-5) wise tricarboxylic acid cycle activity, for entry into the and can inhibit 7,12-dimethylbenzaanthracene induced electron transport chain to produce ATP (Armstrong and mammary tumorigenesis in female rats (Singletary K, Mac Frank, Biochemistry-Second Edition, New York, Oxford Donald C, Wallig M. Cancer Lett. 1996 Jun. 24; 104(1):43 University Press Inc., 1983). In cancer cells, the predomi 8). The use of rosemary has been used in formulations nant fate of pyruvate is lactic acid through activity of LDH described in patent publications that demonstrate a range of in the cytosolic compartment. And, to ensure little to no side products such as antimicrobial agents (U.S. Pat. No. 6,846, effects-the formulation should not affect the remainder of 498, Jan. 25, 2005, De Ath, et al.), an aid to quit Smoking the glycolytic pathway—which is a common ground (U.S. Pat. No. 6,845,777, Jan. 25, 2005, Pera), antioxidant between cancer and the host. While the substitution of any sunscreen (U.S. Pat. No. 6,831,191, Dec. 14, 2004, specific LDH inhibitor would be effective, we tested a range Chaudhuri), nutritional supplement formulations (U.S. Pat. of polyphenolic compounds and herbal extracts for efficacy No. 6,827,945, Dec. 7, 2004, Rosenbloom), foods and in inhibiting the LDH enzyme directly. Some flavonoids personal care products (U.S. Pat. No. 6,844,020, Jan. 18, were not as potent as others. For example Sesamol, apigenin, 2005, Johnson et al.) and for the treatment of skin disease rutin and dioSmin exhibited mild to no effect, where as (U.S. Pat. No. 6,800,292, Nov. 5, 2004, Murad), diabetes 2,3,4'5,7-pentahydroxyflavone (herein also referred to as (U.S. Pat. No. 6,780,440, Aug. 24, 2004, Naguib), allergies “morin'), was fairly potent and effective. Prior art relating to (U.S. Pat. No. 6,811,796, Nov. 2, 2004, Yoshida), ulcers the Specific use of morin has described its use either alone (U.S. Pat. No. 6,638,523, Oct. 28, 2003, Miyazaki, et al.), or in combination with other flavonoids in patent publica inflammatory disorders (U.S. Pat. No. 6,541,045, Apr. 1, tions for antimicrobial agents (JP2004250406. Sep. 9, 2004, 2003, Charters, et al.), pain (U.S. Pat. No. 6,444.238, Sep. 3, Danno Genichi and Arima Hidetoshi), treatment of diaper 2002, Weise) and psoriasis (U.S. Pat. No. 6,403,654, Jun. 11, rash (JP2004.091338, Mar. 25, 2004, Tamura Kokichi), an 2002, De Oliveira). anti-tumor agent (JP2001055330, Feb. 27, 2001, Tanaka Takuji), substances that control plant fertility (U.S. Pat. No. 0018) Myrrh can also be used for/or adjunct to the LDH 5,733,759, Mar. 31, 1998, Taylor Loverine and Mo Yinyuan) inhibitor component. Myrrh is primarily known for its and treatment of chlamydial infection (CA 2419716, Feb. anti-parastic (Massoud AM, El Ebiary FH. Abou-Gamra M 21, 2002, Vuorela, Pia et al.) or radiation dermatitis (U.S. M, Mohamed GF, Shaker S M., J. Egypt Soc Parasitol. 2004 Pat. No. 6,753,325, Jun. 22, 2004, Rosenbloom). Moreover, December; 34(3 Suppl): 1051-76; Soliman O E, El-Arman research Studies have demonstrated the efficacy of morin M, Abdul-Samie ER, El-Nemr HI, Massoud A.J Egypt Soc against proliferation of carcinoma cells through a mecha Parasitol. 2004 December; 34(3):941-66) anti-microbial (El nism thought to involve inactivation of the cell cycle kinase Ashry E S, Rashed N, Salama O M, Saleh A. Pharmazie. and activation of the mitogen/stress pathway kinases (Brown 2003 March; 58(3):163–8) and anti-fungal properties J, O'Prey J, Harrison P R., Carcinogenesis. 2003 February; (Dolara P. Corte B, Ghelardini C, Pugliese AM, Cerbai E, 24(2):171-7) and inhibition of topoisomerase I (Boege F. Menichetti S, Lo Nostro A Planta Med. 2000 May; Straub T, Kehr A, Boesenberg C, Christiansen K, Andersen 66(4):356-8). And, although there is research investigating A, Jakob F, Kohrle J., J Biol. Chem. 1996 Jan. 26; its use against infections, there is little to no experimental 271(4):2262-70). Pentaallyl ethers of morin are also known research describing its use in the treatment of cancer. On the to be anti-tumor agents, which can inhibit p-glycoprotein other hand, a number of patent publications have described ATP efflux of chemotherapy drugs in drug resistant cells the use of myrrh in complex chinese medicinal herbal (Ikegawa et al., Cancer Letters: 2002; 177: 89-93). Our formulations to treat cancer (WO 00/50053, Feb. 29, 1999, Studies Suggest a possible role for morin in antagonizing the Sofer et al., US2004219226, Nov. 4, 2004, Lee et al.; function of LDH. CN1413659, Apr. 30, 2003, Changkui; CN1448164, Oct. 15, 2003, Wenxiu; CN1302622, Jul. 11, 2001, Fangy; 0.017. In addition, we screened a large number of herbal CN1237447, Dec. 8, 1999, Shaoxian; CN1203801, Jan. 6, alcohol extracts for LDH inhibition. While many herbal 1999, Ruifen and Fengxiang; U.S. Pat. No. 5,876,728, Mar. compounds Such as fenugreek, ginseng, dill, anise, carda 2, 1999, Kasset al.; CN1151293, Jun. 11, 1997, Fawang and mom, peppermint, chamomile, basil and cilantro were not Qing; CN1133725, Oct. 23, 1996, Tang; CN1107351, Aug. effective, ethanol extracts of rosemary (ROSmarinus Ofici 30, 1995, Fang et al., CN1061908, Jun. 17, 1992, Yang et nalis) and myrrh (Commiphora myrrha) were cytotoxic and al.; CN1058911, Feb. 26, 1992, Chen). Moreover, the use of effective in providing LDH inhibitory effects. While there myrrh has been described in patent publications describing are meager patent publications that describe the use of a range of products Such as appetite Suppressant toothpaste rosemary for the treatment of cancer, experimental research (CA2485562, Jun. 10, 2004, Zuckerman), deodorant corroborates its capacity to antagonize tumor growth. For (JP2004160216. Jun. 10, 2004, Imanaka), burn ointment example carnoSol, a phenolic compound extracted from (CN1440775, Sep. 10, 2006, Xiao et al.), arthritis medica rosemary, is toxic against acute lymphoblastic leukemia tion (CN1438001, Aug. 27, 2003, Chen), massage oil cells (Dorrie J, Sapala K, Zunino SJ, Cancer Lett. 2001 Sep. (CN1449785, Oct. 22, 2003, Li), anti-viral agents (WO 10; 170(1):33-9), human epithelial cell lines (Mace K, 99/38522, Jan. 29, 1999, Preus and Dzieglewsak), animal US 2006/0035981 A1 Feb. 16, 2006 foods (U.S. Pat. No. 6,652,892, Nov. 25, 2003, McGenity, et (50) (C) 2,3,4'5,7-pentahydroxyflavone or an analogous al.) and soaps (U.S. Pat. No. 6,680,285, Jan. 20, 2004) to alternative capable of inhibiting lactic acid dehydrogenase name a few. and (D) any chemical(s) or Substance(s) that are capable of inhibiting one or more of acetate-coA ligase, malate Syn 0019 Black walnut (Juglans Nigra) extract was also thase, isocitrate lyase, aconitase, phosphoenolpyruvate car found to be a potent LDH inhibitor. However, it inherently boxylase/carboxykinase, glycolate oxidase, phosphoglyco contains compounds Such as 5-hydroxy 1,4-napthoguinone, late phosphatase, glycolaldehyde dehydrogenase, pyruvate which upon further analysis were found to inhibit pyruvate carboxylase, citrate lyase, ferridoxin oxidoreductase, fruc kinase. The inhibition of pyruvate kinase could render tose 1,6-bisphosphatase, 2,3-diphosphoglycerate mutase, potential toxic side effects to the host. Therefore, future propionyl CoA carboxylase, malic enzyme, acetyl CoA research would be required to identify chemicals in black carboxylase and ribulose-1,5-bisphosphate carboxylase. The walnut extract that could specifically inhibit LDH, without combination of these compounds can be Strategically used to altering the remainder of the glycolytic pathway. Although favor oxidative decarboxylation reactions, Suppress the con there is little documentation in either research or patented version of non-glucose carbon based compounds through literature, historical herbal literature indicates that black gluconeogenesis and initiate collapse of glycolysis in tumor walnut is known to treat intestinal parasites, worms, warts, tissue, a chemical manipulation that should be non-toxic or growths, eczema, psoriasis, lupus, herpes, and skin parasites. perhaps even beneficial to normal respiring host tissue. A 0020 Herbal Substances such as rosemary and myrrh are preliminary formulation has been pilot tested, demonstrating comprised of polyphenolic compounds that have intrinsic anti-tumor activity and efficacy comparable to tamoxifen (in anti-oxidant, antimicrobial and anti-inflammatory properties vitro) and taxolf (in vivo), showing no adverse effects on (Theoharides TC, Alexandrakis M. Kempuraj D, Lytinas M. the animal as determined by weight, behavior, food/water IntJ Immunopathol Pharmacol. 2001 September, 14(3):119 intake or excretory function. 127; Makris D P. Rossiter J. T. J. Agric Food Chem. 2001 July; 49(7):3370-7; Aggarwal B B, Shishodia S. Ann NY BRIEF DESCRIPTION OF THE DRAWINGS Acad. Sci. 2004 December; 1030:434-41; Lai P K, Roy J. 0022 FIG. 1 Summary of results-Re: Mazzio and Soli Curr Med. Chem. 2004 June; 11(11): 1451-60). For this man, Biochem Pharmacol. 67:1167-84, 2004. The following reason, polyphenolic compounds, herbs and Spices are Schematic is a brief description Summarizing the findings in known to have robust therapeutic value against a large range this study. Briefly, the paper describes the function of of inflammatory disorderS Such as diabetes, allergies, car ubiquinone (50) in augmenting the kinetic activity of mito diovascular disease, infections, retinopathy, Septic shock, chondrial complex II in cancer cells, while having no neurodegenerative disorders, liver disease, cataracts, peri positive effect on mitochondrial respiration. On the other odontal disease and arthritis, which have been described in hand, riboflavin appears to control the kinetic activity of a plethora of research publications (Alt Med Rev 1996; complex I, which drastically potentiates the rate of mito 1(2):103-111). Moreover, a study examining 50 patented chondrial oxygen consumption through complex IV. These polyphenolic plant derived drugs also describes formula findings describe the inverse relationship between a reduc tions that contain over 685 Species of plants in defined tion in mitochondrial oxygen consumption (ie. mitochon treatments for inflammatory disorderS Such as arthritis, rheu drial poisons), and anaerobic ambient conditions that foster matism, acne skin allergies and more (Darshan S, Dore enhanced glycolytic activity, leading to metabolic activa swamy R., Phytother Res. 2004 May; 18(5):343-57), indi tion, glucose depletion and cell death by Starvation. Con cating the broad spectrum of utility for this class of versely, a rise in ambient oxygen concentration or enhanced compounds for the treatment of diseases other than cancer mitochondrial oxygen consumption (riboflavin) appears to (Arts and Hollman, Am J Clin Nutr. 2005 January; 81 (1 disrupt glycolysis or glucose utilization. Further, neuroblas Suppl):317S-325S). In summary, this invention entails a toma cells have the ability to thrive under completely holistic method for preventing and treating cancer by using anaerobic conditions (ie. in the presence of mitochondrial a specific combination of chemicals or agents that target poisons such as MPP+, in the absence of O, or the removal Specific means in order to Switch the body's metabolism to of dissolved O with dithionite) given that glucose Supply is an aerobic State, thereby specifically blocking glucose Sustained. Briefly, our findings indicate that the mode of metabolism in the tumor. MPP+ toxicity in a blastoma cell model for the study of Parkinson's disease occurs through the propelling of anaero BRIEF SUMMARY OF INVENTION bic glucose metabolism leading to Subsequent depletion of glucose Supply and cell death by Starvation. These findings 0021. The present invention is directed to a composition may be relevant to the Study of cancer as they demonstrate and method of treating cancer. The embodiment discloses a the dependency of malignant cells to derive ATP solely natural pharmaceutical formulation designed to exploit the through Substrate level phosphorylation and the adverse Vulnerability of cancer tissue with regards to its anaerobic effects of optimized mitochondrial function on anaerobic requirement for non-Oxidative phosphorylation of glucose to glycolysis. derive energy, which is in direct opposition to the host. The formulation is intended to target central pathways that 0023 FIG. 2 The toxicity of selected plant extracts and should block the use of glucose for production of ATP only 2,3,4'5,7-pentahydroxyflavone were previously determined in cancer cells. More particularly, the composition of this on N-2A neuroblastoma cells prior to examination of their invention is comprised of a combination of one or more of effects on kinetic activity of pyruvate kinase (PK) and LDH the following (A) 2,3-dimethoxy-5-methyl-1,4-benzo (data not shown). Briefly, the effects of experimental com quinone, ubiquinones (5-45) (B) compound(s) or Sub pounds on PK and LDH Type V, resembling that inherent to stance(s) capable of augmenting oxidative phosphorylation human cancer (Koukourakis et al., Br J Cancer. 2003; Such as a riboflavin containing compound and/or ubiquinone 89:877-85; Augoff and Grabowski. Pol Merkuriusz Lek US 2006/0035981 A1 Feb. 16, 2006
2004; 17:644-7; Nagai et al., Int J Cancer. 198815;:10-6; A Stock Solution of each experimental compound was pre Evans et al., Biol. Chem. 1985; 260:306-14) were deter pared in HBSS containing 5 mM HEPES, adjusted to a pH mined in pure isolated enzyme preparations. Briefly, PK of 7.4. After 24 hours incubation at 37° C. and 5% CO/ Type III (from rabbit muscle 2.7.1.40) was prepared in atmosphere almar blue indicator dye was used to assess cell distilled water+HEPES (pH 7.5), at a concentration of 0.5 Viability. Quantitative analysis of dye conversion was mea enzyme U/ml. Pyruvic acid was converted to lactate in the sured on a microplate fluorometer-Model 7620-version presence of LDH (from rabbit muscle, type V-S LEC 5.02, Cambridge Technologies Inc. with settings fixed at 1.1.1.27), at a concentration of 10 U/ml in the presence of 550/580), excitation/emission, wavelengths. The data are adenosine, 2',5'-diphospahte (ADP) (1.5 mM), 3-NADH (1 expressed as the meantS.E.M., n=4, and the Significance of mM)+magnesium sulfate (MgSO) (5 mM). Experimental difference from the controls was determined by a one way compounds were incubated with the enzyme solution for 10 ANOVA, followed by a Tukey mean comparison post hoc minutes and addition of 1 mM phosphoenolpyruvate (PEP) test (*=P<0.001). prepared in distilled water Started the reaction. Negative 0025 FIG. 4A describes the effect of a natural pharma controls were established for all compounds tested. Enzyme ceutical formulation (NPF) on MD-MB-231 mammary car activities were determined by Spectrophotometric analysis cinoma in Nu/Nu female mice. Briefly, 6 week old female using a UV spectrometer at 340 nm, by monitoring the Nu/Nu mice were kept in an autoclaved micro isolator cage, oxidation of NADH. Experimental compounds that blocked maintained under pathogen free conditions. The tumors the reaction through the PK/LDH cascade, were re-analyzed were ascetically Surgically removed and transferred to a for LDH inhibition. LDH activity was achieved using an sterile Petri dish containing RPMI-1640. The homogenate enzyme reaction mixture, minus PK or PEP, and starting the was centrifuged, pelleted, resuspended into a concentration reaction with pyruvate (1 mM) prepared in buffered distilled of 10 million cells/ml and injected into the mammary fat water. Validation studies for LDH kinetic activity were pad. The tumors were established by day 9 after implant and established by monitoring the oxidation of NADH over time treatment began. The formula was prepared in Sterile Saline, and concentration with dual detection quantifying lactic acid and administered by i.p. injection for 3 days and S.c for the using a lactate oxidase based calorimetric enzymatic assay next 3 days, stopping at day 15. Taxol-(24 mg/kg in 2% (Procedure No 735, Sigma Diagnostics, St. Louis, Mo.). PEG 300, 8% cremophor CL an 80% sterile Saline) was FIG. 2A describes the effect of tumoricial plant extracts and administered i.v. Intermittently up to day 19 (days 10, 13, 16 2,3,4'5,7-pentahydroxyflavone on inhibition of PK/LDH and 19). Since there were no signs of toxicity with the activity. The data represent reaction rate of NADH oxidation formulation, to gain greater understanding as to the effects in the presence of enzyme/cofactor reagents+PEP (1 of this drug, the dose was increased to 1.5x and 2x for two mM)-varying concentration of experimental compounds at regimens implemented at day 35, and 37 of the tumor 30 Min. The data are expressed as the Mean+S.E.M., (n=4). implantation. The data represents tumor Volume estimation Significance of difference from the controls were determined (mm3) and expressed as the meantS.E.M., n=4, for treat by a one-way ANOVA, followed by a Tukey mean com ment groups, with n=1 for the control. FIG. 4B describes the parison post hoc test, *group P-0.001, *P-0.001. FIG.2B effect of a NPF treatment on weightloss, behavior and describes the effect of tumoricial plant-extracts and 2',3,4'5, health. There were no deaths reported in the experiment due 7-pentahydroxyflavone on inhibition of LDH activity. The to toxicity. The control animals had a moderate weight gain data represent reaction rate of NADH oxidation in the within the acceptable limits for normal growth. There was a presence of enzyme/cofactor reagents+pyruvate (1 loSS of weight with in the taxol treatment group. In a mM)+single level of experimental compound over time. The comparison chart, animals treated with the formulation data are expressed as the Mean-tS.E.M., (n=4). Significance showed no weight loss. The formulation was well tolerated of difference from the control was determined by a two-way by the animals in the dosing regimen, and showed no signs ANOVA, *)P-0.001. of toxicity. The food and water intake was normal and the 0024 FIG. 3A describes the evaluation of 3-bromopy Same for the excretory functions. The animals showed no ruvate (3-BP) versus 2,3-dimethoxy-5-methyl-1,4-benzo other behavioral changes. The data represents weight gain quinone (2,3-DMBQ) on growth inhibition of MCF-7 mam (g) and are expressed as the meantS.E.M., n=4, for treat mary carcinoma cells. Briefly, cells were grown in Eagles ment groups, with n=1 for the control. Treatment period MEM medium with 20 mg insulin/ml and 10% calf serum and plated at 5' 104 cells in 24 well plates. Appropriate positive (tamoxifen) and negative (no drug) controls were DETAILED DESCRIPTION OF THE maintained simultaneously. After 24 hour incubation, cells PREFERRED EMBODIMENT were trypsined and collected by centrifugation, re-SuS 0026. The embodiment of the present invention relates to pended in fresh media and cells were counted using trypan a holistic chemotherapy agent for treatment of cancer in blue dye on a hemacytometer. The data are expressed as the humans and animals. AS Summarized from the background meantS.E.M., n=3, and the significance of difference from literature and experiments as described above, the formula the controls was determined by a one way ANOVA, fol tion attempts to shift the body toward a more aerobic State, lowed by a Tukey mean comparison post hoc test which should be lethal to cancer but beneficial to the host. (*=P<0.001). FIG. 3B represents the evaluation of 3-BP Briefly, 2,3-dimethoxy-5-methyl-1,4-benzoquinone versus 2,3-DMBQ on cell viability in N2A neuroblastoma (ubiquinone (0)) herein termed “DMBQ" and the short chain cell line. Briefly, the experimental media consisted of ubiquinones appear to adversely target a predominant cyto DMEM (without phenol red), supplemented with 1.8% FBS Solic anaerobic metabolic pathway involving the conversion (v/v), penicillin (100 U/ml)/streptomycin (0.1 mg/ml), 4 of non-glucose carbon based Substrates into glucose. mM L-glutamine and 20 uM sodium pyruvate. Cells were Ubiquinone (50) plays an important role in oxidative phos plated at approximately 0.5x106 cells/ml in 96 well plates. phorylation where it shuffles electrons to flavoprotein US 2006/0035981 A1 Feb. 16, 2006 enzymes (requiring FMN prosthetic groups) and cyto latency in comparison to a vehicle control. Unlike taxolf, chromes, and translocateS protons to generate a proton where there was weight loSS observed during treatment, motive force by which to propel oxidative phosphorylation administration of the formulation accompanied no sign of and aerobic production of ATP Riboflavin, FAD and FMN toxicity, behavioral changes or weight loSS in test animals. play a paramount role in electron transport, the function of The formulation was well tolerated, where food and water ubiquinone oxidoreductases, the facilitation of aerobic intake, behavior and excretory functions were maintained at metabolism of glucose, and can increase O utilization by a normal level. The animals showed no other behavioral the mitochondria in cancer cells in excess of 400%, all changes. The route of administration in this Study was S.c. which correspond to the impedance of anaerobic glycolysis and ip, indicating the formulation would be powerful if in cancer cells (Mazzio and Soliman, Biochem Pharmacol. administered iv, like taxol. Further, the formulation is effec 67:1167-84, 2004; publication summary of FIG. 1. Further, tive in its water-soluble form, yet readily modifiable to suit we have evaluated a number of compounds that are capable a large range of Solubilities based on the number of Side of inhibiting LDH-5 (the isoform most resembling that chain units associated with the quinoid base. This fulfills a inherent to human) (Koukourakis et al., Br J Cancer. 2003; current need to establish treatment that does not require 89:877-85; Augoff and Grabowski. Pol Merkuriusz Lek emulsifying agents or Solubilizing vehicles (ie crema 2004; 17:644-7; Nagai et al., Int J Cancer. 198815;:10-6; phor(R), which can lead to further complications Such as Evans et al., Biol. Chem. 1985; 260:306-14), some of which hyperSensitivity reactions. are displayed in FIG. 2. Moreover, individual components of the formulation were tested in vitro at Florida A & M 0028 More definitively, the active component(s) of the University using neuroblastoma models from various Spe formula are comprised of a combination of one or more of cies, and at the University of Miami, using MCF-7 cell line the following: A) 2,3-dimethoxy-5-methyl-1,4-benzo derived from the pleural effusion of a female patient with quinone, ubiquinones (5-45), their corresponding analogues, metastatic breast carcinoma (FIGS. 3A,B). Both report simi derivatives or prodrugs B) any chemical (S), Substance(s) or lar effects on all compounds tested (data not shown) and the agent(s) capable of augmenting mitochondrial oxidative effects of DMBQ were >50x more toxic than bromopyru phosphorylation herein termed “OXPHOS (+)”, such as Vate, which is currently considered a cancer breakthrough riboflavin (vitamin B2) and its derivatives, flavin adenine due to its lethal effects on certain types of tumors, with little dinucleotide, flavin mononucleotide or analogs and/or observable toxic effects to the host (BBC News, Jul. 16, ubiquinone (50) and C) 2,3,4,5,7-pentahydroxyflavone or a 2002). While we only show the data for DMBQ, all com Suitable alternative Such as chemicals(s), Substances (S), pounds had tumoricidal properties, and additive effects of agent(s) or extract(s) capable of inhibiting LDH, herein LDH inhibitors and flavin derivatives lowered the LCso of termed “LDH (-)”. The term OXPHOS (+) is further defined DMBQ. Additionally, preliminary studies in our lab indi as any chemical(s), Substance(s) or agent(s) that can aug cated that 3-bromopyruvate was not an inhibitor of LDH-5 ment or contribute to the function of NADH:ubiquinone at any concentration where the compound exhibited tumori oxidoreductase (complex I), Succinate dehydrogenase-CoQ cidal properties, Suggesting its effects are through an oxoreductase (complex II), ubiquinol:cytochrome c oxi unknown mechanism, independent of LDH. Oddly, other doreductase (complex III), cytochrome c oxidase (complex known LDH-5 inhibitors such as oXamate were ineffective IV), ATP synthase (complex V), the Krebs cycle and mito in inhibiting LDH or inducing toxicity Suggesting that much chondrial respiration either directly or indirectly. These include metabolic precursors or compounds required for the more research will be required to Synthesize and evaluate biosynthesis of coenzyme Q10, Krebs cycle or respiratory Specific LDH inhibitors as anti-cancer agents. The combi enzymes or the function thereof. For example constituents nation of the Substances that comprise this invention, should required for decarboxylation reactions/pyruvate dehydroge augment the concentration of pyruvate and its utilization for nase activity Such as thiamin, biotin, pantothenate or lipoic aerobic mitochondrial cell respiration in normal cells, while acid, constituents required for ubiquinone Synthesis Such as blocking anaerobic energy production from glucose in can tyrosine, tetrahydrobiopterin (THB), vitamins B2, B6, B12, cer cells. In brief overview, while there could be many folate, niacin, Vitamin C, pantothenic acid (Folkers et al., mechanisms involved with observed efficacy, it is the intent Biochem Biophys Res Commun 1996 244: 358-363) and that the formulation shift the metabolism of the host toward ubiquinone metabolic precursors including para-hydroxy a more aerobic state thereby specifically blocking ATP benzoate, para-hydroxycinnamate, para-hydroxyphe production in the tumor. nylpyruvate, para-hydroxyphenylactate, polyprenyl-para 0027. A working example comprised of a tri-fold formu hydroxybenzoate, tyrosine, phenylalanine and isopentyl lation containing an active ingredient from each of the diphosphate. The determination of compounds to be primary classified components as listed above, was analyzed included in the OXPHOS (+) component, can be assessed by for efficacy against a tumor model in mice. These data effects on the function of mitochondria/enzymes derived present Specifically the efficacy, utility and Substantial effect from any relevant Source including but not limited to bac of a test formulation which consisted of riboflavin, 2,3- teria, animal, plant, yeast, mold or tumor. The term LDH (-) dimethoxy-5-methyl-1,4-benzoquinone and 2,3,4,5,7-pen is further defined as any compound(s), chemical(s) or tahydroxyflavone. The preliminary formulation was submit agent(s) that can inhibit preferably LDH-5, the LDH inher ted to Kard Scientific (Boston, Mass.) for a small pilot study ent to cancer, as well as any other pertinent isoforms that can to determine efficacy against MD-MB-231 human mam be used experimentally and relate to the LDH in cancer, mary carcinoma in a Xenograft model using Nu/Nu nude including that derived from any Source including but not mice (FIGS. 4A,B). In this study, two treatment groups were limited to plant, bacteria, yeast, mold, fungus, animal or established and consisted of the formulation and taxol.E), tumor. The LDH (-) component should be capable of both compared to a non-treated control. Both taxole) and the inhibiting the LDH enzyme inherent to cancer or LDH-5 formulation showed a reduced tumor growth and growth also termed “LDH-V”, at concentrations that juxtapose US 2006/0035981 A1 Feb. 16, 2006
tumoricidal effects, indicating the mechanism of action 0032. In structure, coenzyme Q resembles vitamin K involves inhibition of LDH. Additionally, a further compo (base nucleus: 2-methylnaphthoquinone), the plastoquino nent herein termed anaerobic inhibiting component "AIC nes (base nucleus: 2,3-dimethylbenzoquinone), toco (-) can also be incorporated into the invention, being pherolduinones (base nucleus: 2,3,5-trimethylbenzo defined as compounds(s) or substance(s) other than DMBQ, quinone) and menoquinone (base nucleus: 2-methyl-4- that aid in blocking the conversion of carbon-2 intermediates naphthoguinone) in that it possesses a quinone ring nucleus into energy, CO into carbon intermediates or inhibit attached to a hydrocarbon tail (IUPAC definitions-Eur. J. enzymes that utilize CO as a substrate/cofactor. The AIC Biochem. 1975 53: 15-18). The ubiquinone component (-) component is further defined as any agent(s), chemical(s) (being that present in OXPHOS (+) component and/or or Substance(s) that are capable of inhibiting anaplerotic ubiquinones (0-45)), may also be incorporated with or carboxylase enzymes, the glyoxylate shunt, reductive tricar Substituted by plastoquinones or Vitamin E/K quinones. boxylic acid cyle, the calvin-benson cyle or gluconeogenesis Ubiquinones can further include any oxidized or reduced either indirectly or directly, and more specifically, inhibit (ubiquinol) forms Such as CoQ0, ubiquinone (O), ubiquinol/ one or more of the following enzymes: acetate-coA ligase, ubichromenol (O), CoQ1, ubiquinone (5), ubiquinol/ malate Synthase, isocitrate lyase, aconitase, phospho ubichromenol (5), CoQ2, ubiquinone (10), ubiquinol/ enolpyruvate carboxylase/carboxykinase, glycolate oxidase, ubichromenol (10), CoQ3, ubiquinone (15), ubiquinol/ phosphoglycolate phosphatase, glycolaldehyde dehydroge ubichromenol (15), CoQ4, ubiquinone (20), ubiquinol/ nase, pyruvate carboxylase, citrate lyase, ferridoxin oxi ubichromenol (20), CoQ5, ubiquinone (25), ubiquinol/ doreductase, fructose 1,6-bisphosphatase, propionyl CoA ubichromenol (25), CoQ6, ubiquinone (30), ubiquinol/ carboxylase, malic enzyme, acetyl CoA carboxylase, 2,3- ubichromenol (30), CoQ7, ubiquinone (35), ubiquinol/ diphosphoglycerate mutase, and ribulose-1,5-bisphosphate ubichromenol (35), CoQ8, ubiquinone (40), ubiquinol/ carboxylase. ubichromenol (40), CoQ9, ubiquinone (45), ubiquinol/ 0029 Even more definitively, DMBQ, other ubiquinones ubichromenol (45), CoQ10, ubiquinone (50), ubiquinol/ or ubiquinone (50) in the OXPHOS (+) component, can ubichromenol (50) or any other derivative, analog, include their corresponding hydroquinones, ubichromenols, intermediate, precursor or pro-drug to these molecules. ubichromanols or Synthesized/natural derivatives. BenZO 0033. The present invention can include ubiquinones quinones of this family are properly referred to as either (0+) derivatives, analogues, intermediates, precursors and “Coenzyme On' where n designates the number of isoprene prodrugs. Examples include rearrangements, modification, units (also termed "prenyl”) in the isoprenoid side chain, or substitutions of the methyl, methoxy or carbonyl groups or alternatively, "ubiquinone (x)' where X designates the total the isoprenoid Side chain with Substituents Such as alkyl number of carbon atoms in the Side chain. The quinones of groups including branched, cyclic and Straight chain, alky the coenzyme Q Series differ in chemical Structure and form lene, alkoxy, alkenyl, alkaryl, alkynyl, acyl, acylamino, a group of related, 2-3-dimethoxy-5-methyl-benzoquinones acyloxy, cycloalkyl, cycloalkenyl, haloalkyl, aryl Substitu with variation in length of the polyisoprene Side chain. The ents including phenyl, napthyl and Substituted phenyl Sub term “ubiquinone” is represented by the following base Stituents, aralkyl Substituents including benzyl and tolyl Structure: Substituents, halogen Substituents including fluoro, bromo, chloro Substituents, oxygen Substituents including hydroxy, lower alkoxy, ether, carboxyl and ester Substituents, nitrogen Substituents including nitrogen heterocycles, heteroaryls, amides, amines and nitriles, Sulfur Substituents including CHO thiol, thioether, thioalkoxy, thioaryloxy and thioesters and aldehydes, ketones and aromatic hydrocarbons or hydrogen. In addition to altering the methyl, carbonyl group and/or the CHO CH methoxy groups with the above noted Substituents, addition, rearrangment, replacement or modification of Substituents also provides ubiquinones that are also included within the Scope of this invention. Accordingly, Small changes resulting wherein R is equal to or greater than 0 isoprene (3-methyl from modification of the Substituents or benzoquinone 2-butenyl) unit (s) nucleus for any improved functionality are included within 0030 For example ubiquinone (5), which corresponds to the Scope of the present invention. Ubiquinones utilized in the Structure: the present invention may be isolated in nature or Syntheti cally produced using any method including known to one skilled in the art, by way of example (Weinstock et al., O CH Journal of Chem Eng Data 1967 12(1) 154-155; Sato et al., Chem. Abst. 78:471, 1993; U.S. Pat. No. 5,254,590, Oct. 19, CHO (CH-CH=CCH-H 1993, Malen et al; JP57021332, Feb. 4, 1982, Kiso Yoshihis; n = 1 U.S. Pat. No. 6,225,097, May 1, 2001, Obata et al; U.S. Pat. No. 6,103,488, Aug. 15, 2000, Matsuda et al.; WO03/ CHO CH 056024 Dec. 27, 2002 Yajima, K; JP57021332, Feb. 4, 1982 Kiso Yoshihisa; DE3221506 Dec. 8, 1983, Doetz, Karl Heinz, U.S. Pat. No. 6,545,184, Apr. 8, 2003 Bruce Lipshutz and Paul Mollard; EP1354957, Oct. 22, 2003, Matsuda 0031 wherein n is equal to the number of isoprene Hideyuki et al; JP55159797, Dec. 12, 1980, Hasegawa units Yasuhiro), all of which could be incorporated by reference. US 2006/0035981 A1 Feb. 16, 2006
One of ordinary skill in the art will appreciate that changes and aromatic hydrocarbons. Accordingly, Small changes may be made to the ubiquinone structure for improved resulting from addition, modification, rearrangment or functionality to form a derivative without taking away from replacement of the Substituents or base Structure are the tumoricidal function thereof. In embodiments of the included within the scope of the present invention. Further, present invention, ubiquinones (0-45)+the OXHPHOS (+) while it is doubtful that riboflavin and ubiquinone (50) alone ubiquinone (50) can comprise from about 0 to about 100 could effectively place cancer in remission without adjunct weight percent (herein referred to as “wt %”) based on the chemotherapy or DMBQ, the use of a natural or synthetic total weight of the invention composition. More particularly, potent AIC (-) or LDH (-) may in and of itself be effective. ubiquinones could be present in an amount of from about 30 For that reason, the metes and bounds of the invention and to about 80 wt %, and more specifically in an amount of claims delineate the AIC (-) or LDH (-) to be from 0-100% about 54 wit wt of total composition and can exist in combination with an 0034. The formulation can further include in its OXPHOS (+) component (ie. riboflavin and ubiquinone OXPHOS (+) component, a riboflavin containing com (50))+DMBQ, which can vary to maximize efficacy. pound, Such as riboflavin, its pharmaceutically acceptable 0036) In embodiments, an LDH (-) component can be salts and derivatives: flavin mononucleotide (FMN), flavin present in an amount from about 0 to about 100 wt % of the adenine dinucleotide (FMN) or any other synthesized or total composition. More particularly, if combined with natural derivative. In embodiments, the present invention ubiquinoneS+a riboflavin containing compound, the LDH includes a riboflavin containing compound or OXHPHOS (-) can be present in an amount of from about 10 to about (+) in an amount of from about 0 to about 100 wt % of the 50 wt %, and even more specific in an amount of about 13 invention composition. More particularly, riboflavin or wt %. It is important to mention that future research will be OXHPHOS (+) can be present in an amount of from about required to delineate maximum efficacy of therapeutic com 15 to about 35 wt %, and more specifically in an amount of binations and ranges. And, although our in Vivo animal Study about 33 wt %. A riboflavin containing compound can also incorporated the LDH (-) at 13%, we have further estab include compounds represented by the following base Struc lished evidence of the importance of this component, and its ture including its derivatives, intermediates, analogs, pre concentration above 75-80% may prove valuable. The LDH cursors and prodrugs including but not limited to 5-amino (-) can be morin (2,4,5,7-pentahydroxyflavone), which cor 6-(5-phosphoribitylamino)uracil, 6,7-Dimethyl-8-(1-D- responds to the following Structure and includes its deriva ribityl)lumazine, ribitol, lumichrome and 5,6- tives, analogues and pro-drugs: dimethylbenzimidazole. The term riboflavin is represented by the following base structure: HO OH
HO O CH
OH
CH OH O
The LDH (-) may also be any chemical, polyphenolic or plant extract capable of inhibiting preferably LDH-5, any isoform of LDH inherent to cancer tissue, or any other relevant isoform of LDH. And the LDH inhibitor component can be any Synthesized or natural chemical, which is intended for the purpose of inhibiting LDH to treat any type of cancer. If the LDH inhibitor is a polyphenolic compound, where in the isoalloxazine ring System of riboflavin contains it can further include phenolic acids (benzoic acid or cin methyl groups at C and C and a ribityl group at N'. namic acid derivatives), benzofurans, chromones, cou 0.035 Examples of riboflavin derivatives can include marins, phenylacetic acids, phenols, phenylpropanoids, Xan rearrangements, modifications, Substitutions of the methyl, thones, Stilbenes, quinones and flavonoids or corresponding carbonyl, amino or ribityl group groups with additional derivatives, analogues and pro-drugs (Naczk and Shahidi, Substituents Such as Such as alkyl groups including Chromatogr A. 2004 Oct. 29; 1054(1-2):95-111). If the LDH branched, cyclic and Straight chain, alkylene, alkoxy, alk inhibitor is a flavonoid, it may be further characterized in enyl, alkaryl, alkynyl, acyl, acylamino, acyloxy, cycloalkyl, that the Structure is a aurone, flavone, isoflavone, flavanone, cycloalkenyl, haloalkyl, aryl Substituents including phenyl, isoflavanone, catechin, flavan, flavanonol, chalcone, antho napthyl and Substituted phenyl Substituents, aralkyl Substitu cyanidin, anthocyanin, proanthocyanidin, flavanol, flavonol, ents including benzyl and tolyl Substituents, halogen Sub isoflavonol or biflavonoid moiety or corresponding deriva Stituents including fluoro, bromo, chloro Substituents, oxy tives, analogues and pro-drugs. One skilled in the art of gen Substituents including hydroxy, lower alkoxy, ether, bioflavonoids will recognize that a large number of com carboxyl and ester Substituents, nitrogen Substituents includ pounds, both glycosides and aglycones, also fall within the ing nitrogen heterocycles, heteroaryls, amides, amines and Scope of the present invention (Prasain et al., Free Radic nitriles, Sulfur Substituents including thiol, thioether, thio Biol Med. 2004 Nov. 1; 37(9): 1324-50; Kris-Etherton et al., alkoxy, thioaryloxy and thioesters and aldehydes, ketones Am J. Med. 30, 71S-88S. 2002). And while morin was US 2006/0035981 A1 Feb. 16, 2006
selected based on LDH specificity, other flavonoids such as luteolin, roSmadial, roSmanol, roSmaric acid, rosemaricine, epigallocatechin gallate and quercetin, as well as thiol roSmarinic acid, roSmarinol, roSmariquinone, Safrole, Salvi oxidizing agents can effectively inhibit LDH, and may be genin, thymol, anethole, carveol, myrtenol, pinocarveol, Substituted for/or combined with morin. It should be under urSolic acid, Verbenol, Verbenone, Zingiberene, b-caroteine, stood that the LDH (-) compound of the present invention geraniol, 7-b-amyrenone, 7-ethoxy-roSmanol, hispidulin, can be administered in any pharmaceutically acceptable form including, Salts, esters, ethers, derivatives and ana isoborneol, isopinocarveol, isoroSmanol, isoroSmaricine, logues thereof. The LDH (-) component may also be an labiatic acid, ledene, linalol, luteolin-7-glucoside or whole extract of/or any form of/or any chemical constituent (s) extracts of rosemary as processed under any procedure. inherent to any plant species of myrrh, rosemary or black walnut and combinations thereof. It was also noted that 0039. Optional active chemical constituents within black extract of Sage (Salvia officinalis), clove (Syzygium aromati walnut may include but are not limited to: 2-methyl, 1,4- cum), nutmeg (Myristica fragrans) licorice (Glycyrrhiza napthoguinone, 2,3-dihydro-5-hydroxy-2-methyl-1,4 uralensis), corriander Seed (Coriandrum Sativum), eucalyp napthalenedione, 5-hydroxy-2-methyl-1,4-napthoguinone, tus leaf (Eucalyptus globules), cinnamon (Cinnamomum 5-hydroxy-3-methyl-1,4-napthoguinone, 2,3-dimethyl-5- cassia), ginger root (Zingiber officinale), and green tea also hydroxy-1,4-napthoguinone, and 2,3-dihydro-5-hydroxy-1, effectively inhibited LDH enzyme activity. Therefore, either 4-napthalenedione, 1,4-napthoguinone or whole extracts of whole extracts or chemical constituents inherent to these black walnut as processed under any procedure. herbs can also be incorporated, Substituted for/or combined as the LDH (-) component. Whole herbal components can 0040. The formulation may comprise one or more of a further be prepared by extraction or drying procedures. Any combination of the aforementioned to optimize efficacy, portion of the plant can be used, not limited to the root, Seed, however the following are Some examples as would apply to nut, Stalk, bark, vegetable, fruit, hull, bud, leaf, flower, bulb humans. The term “OXPHOS (+)" represents mitochondrial or entire plant. Pure fresh herbs are typically dried at very low temperature, and macerated into an extract, comprised augmenting component, “LDH (-)” represents the LDH of one or more of the following: grain alcohol, distilled inhibitor component and “AIC (-)' represents a compound water, glycerine or vinegar. These also include any liquid, other than DMBQ capable of inhibiting the metabolic chemical, alcohol, lipophilic oil based Solvents or acetone. enzymes or pathways as previously defined. DMBQ or the Depending upon the Strength of the herbal extract, dry herb AIC (-) can be present at between 0-100%, the broad range menstrumm ratios can vary (w/v) between 1:5-4:5. Typically is not necessarily limited by the upper limit and the “*” herbal extracts are stored in a sterile closed container (glass represents components of the formulation that were used in or Suitable), in a warm dry area, away from light for about animals or humans. 0.5-2 weeks with intermittent stirring. The extract is then filtered to remove particulates and Stored at a cool tempera EXAMPLE 1. ture in an amber container to prevent exposure to light. While any suitable LDH inhibitor can be used or substituted 0041) in the formulation, the following chemicals derived from specific extracts may be further evaluated for LDH inhibi tion and optionally Selected. 0037 Optional active chemical constituents within myrrh Broad Narrow may include but are not limited to: creSol, cadinene, campes Constituents Range Units Range Units terol, lindestrene, heerabomyrrhol, commiferin, furanodi ene, a-bisabolene, a-commiphoric acid, lindestrene, a-heer OXPHOS (+) abomyrrhol, a-amyrone, germacrene, b-pinene, isofuranogermacrene, cinnamaldehyde, elemol, eugenol, Ubiquinone (50) 0-1000+ Mgs/day/ 200-400 Mgs/day/ cuminaldehyde, b-bourbonene, b-elemene, curzerenone, human human furanodienone, Y-bisabolene, heerabolene. gamma-elemene, Riboflavin * 0-1000+ Mgs/day/ 100-400 Mgs/day/ beta-bourbonene, beta-elemene, isofuranogermacrene, ger human human macrene, furanoeudesma-1,4-diene, furanoeudesma-1,3-di LDH (-) ene, 2-methoxy furanodiene, 3-epi-alpha-amyrin, 4-O-me thyl-glucuronic-acid, culmic-alcohol, heeraboresene, Rosemary Extract 0-25+ Mls/day/ 10–20 Mls/day/ n-nonacosane or whole extracts of myrrh as processed under human human any procedure. Morin * 0-1000+ Mgs/day/ 100-400 Mgs/day/ human human 0.038 Optional active chemical constituents within rose Myrrh Extract 0-25+ Mls/day/ 10–20 Mls/day/ mary may include but are not limited to: cineole, a-humu human human lene, a-pinene, a-terpinol, 5-hydroxy-4,7-dimethoxyfla DMBQ * + Q(1-3) + 0-1000+ Mgs/day/ Vone, apigenin, bomeol, caffeic acid, calacorene, carvone, AIC (-) human camoSol, caproic acid, camphor, camphene, calamenene, eugenol, myrcene, chlorogenic acid, nopol, nepetrin, picro +FDA approved Salvin, piperitenone, b-elemene, b-fenchene, dioSmin, cad chemotherapy drug alene, bomylene, cineole, cirSilion, cadinene, dioSmetin, a-bisabolol, eriodictiol, eudeSmol, Y-muurolol, genkwanin, * Pilot tested against mammary carcinoma in Nude Mice - comparable to methoxy-roSmanol, a-amorphene, a-amyrin, a-fenchene, taxol - no observable side effects a-Selinene, apigenin-7-glucoside, hesperidin, limonene, Feb. 16, 2006
EXAMPLE 2 0042 -continued Broad Narrow Constituents Range Units Range Units Broad Narrow Constituents Range Units Range Units Folic Acid (Folate) 0-1000+ Mgs/day/ 0.2-1 Mgs/day/ al al OXPHOS (+) B-3 (Niacin) 0-500+ Mgs/day/ 00-400 Mgs/day/ al al Riboflavin * 0-1000+ Mgs/day/ 100-400 Mgs/day/ B-6 (Pyridoxine) 0-1000+ Mgs/day/ 00-400 Mgs/day/ human human al al LDH (-) B-12 (Cobalamin) 0-10+ pigs/day/ 50-400 tug/day/ al al Rosemary Extract * 0-25+ Mls/day/ 10–20 Mls/day/ C (Ascorbate) 0-1000+ Mgs/day/ 00-400 Mgs/day/ human human al al Myrrh Extract * 0-25+ Mls/day/ 10–20 Mls/day/ Magnesium 0-400+ Mgs/day/ 00-400 Mgs/day/ human human al al +DMBQ it (Q1-3) + 0-1000+ Mgs/day/ B-5 (Pantothenate) 0-1000+ Mgs/day/ 00-400 Mgs/day/ AIC(-) human al al B-2 (Riboflavin) 0-1000+ Mgs/day/ 00-400 Mgs/day/ +FDA approved al al chemotherapy drug B-1 (Thiamin) 0-100+ Mgs/day/ 10-100 Mgs/day/ al al * Preliminary findings in humans + chemotherapy indicated the combina Biotin 0-400+ pigs/day/ 00-400 ugs/day/ tion to exhibit anti-cancer effects and blocked the side effects of standard al al chemotherapy. Future research will be required to substantiate these find Lipoic Acid 0-1000+ Mgs/day/ 00-400 Mgs/day/ ings. al al LDH (-) EXAMPLE 3 Rosemary Extract 0-25+ Mls/day/ 10–20 Mls/day/ al al 0043) +Extracts of one or 0-25+ Mls/day/ 10–20 Mls/day/ more of Nutmeg, al al Clove, Cinnamon, Broad Narrow Ginger, Corriander Constituents Range Units Range Units Morin 0-1000+ Mgs/day/ 100-400 Mgs/day/ al al OXPHOS (+) Myrrh Extract 0-25+ Mls/day/ 10–20 Mls/day/ al al Ubiquinone (50) 0-1000+ Mgs/day/ 200-400 Mgs/day/ +DMBQ + Q(1-3) + 0-1000+ Mgs/day/ human human AIC(-) al Riboflavin 0-1000+ Mgs/day/ 100-400 Mgs/day/ +FDA approved human human chemotherapy drug LDH (-) Rosemary Extract 0-25+ Mls/day/ 10–20 Mls/day/ human human 004.5 The types of tumor treated by the formulation can Morin 0-1000+ Mgs/day/ 100-400 Mgs/day/ be that of any organ, tissue or cell, including benign and human human malignant, and in humans or any species of animal. More Myrrh Extract 0-25+ Mls/day/ 10–20 Mls/day/ human human Specifically, the formulation may potentially be used to treat + Extracts of one 0-25+ Mls/day/ 10–20 Mls/day/ or prevent many types of cancers including but not limited or more of human human to: cancer of the skin, breast, colon, kidney, bone, blood, Nutmeg, Clove, lymph, Stomach, gastrointestinal, ovary, prostate, liver, lung, Cinnamon, Ginger, Corriander head and neck, gallbladder, adrenal, brain, central nervous +DMBQ + Q(1-3) + 0-1000+ Mgs/day/ System, bronchial, eye, hypothalamus, parathyroid, thyroid, AIC (-) human pancreas, pituitary, nose, Sinus, mouth, endometrium, blad +FDA approved der, cervical, bile duct and Specific types Such as acute chemotherapy drug lymphoblastic leukemia, acute myeloid leukemia, AIDS related cancers, Burkitt's lymphoma, astrocytomas/gliomas and Hodgkin’s lymphoma. EXAMPLE 4 0046) The term “pharmaceutically acceptable carrier' is defined as any Safe material that acts as a vehicle for delivery 0044) including but not limited to: water, Saline, Starches, Sugars, gels, lipids, waxes, paraffin derivatives, glycerols, Solvents, oils, proteins, talc, glycols, electrolyte Solutions, alcohols, Broad Narrow gums, fillers, binders, cellulose, magnesium Stearate, emul Constituents Range Units Range Units sifiers, humectants, preservatives, buffers, colorants, emol lients, foaming agents, Sweeteners, thickeners, Surfactants, OXPHOS (+) additives, Solvents, lubricants or the like. The pharmaceuti Ubiquinone (50) 0-1000+ Mgs/day/ 200-400 Mgs/day/ cally acceptable carrier includes one or more compatible human human Solid or liquid filler diluents or encapsulating Substances that are Suitable for administration to humans or animals. US 2006/0035981 A1 Feb. 16, 2006
0047 The form of a pharmaceutically acceptable carrier 0050. The formulation of Substances that comprises this used to deliver the treatment to a human or animal is all invention are not necessarily limited to definition by mecha inclusive not limited to a cream, Solid, liquid, powder, paste, nism, Since these agents may also meditate tumoricidal gel, tablet, granule, foam, pack, ointment, aerosol, Solvent, effects through other various means. On the other hand, the tablet, diluent, capsule, pill, drink, liposome, Syrup, Solution, invention discloses a means through a mechanism to treat or Suppository, emulsion, Suspension, dispersion, food, bolus, prevent cancer, by Specifically and intentionally creating a electuary, paste or other bio-delivery System or agent. For formulation that combines one or more compounds classi mulations of the present invention embodiments include fied under OXPHOS (+), AIC (-) and/or DMBQ and LDH pharmaceutically acceptable carriers and delivery Systems (-). The mechanism of manipulating glucose metabolism in adapted for varying route of administration Such as topical, cancer cells through the described approach comprises this enteral and parenteral including but not limited to: oral, invention, and also includes any or all type of modifications rectal, nasal, vaginal, Subcutaneous, intramuscular, intrave or methods to the development of a formula to achieve these nouS, intratumor, intraperitoneal, intramammary, means, that are obvious to one skilled in the art, but not intraoSSeous infusion, transmucosal, transdermal, epicutane described in the aforementioned and adhere to the Scope of ous, intracutaneous, epidural, intrathecal, inhalation, optha the invention. lamic or other Suitable route. Formulations for parenteral administration include aqueous and non-aqueous isotonic What is claimed is: Sterile Solutions, which may contain anti-oxidants, oils, 1. A composition comprising: glycols, alcohols, buffers, bacterioStats, Solutes, Suspending A therapeutically effective amount of one or more of the agents, biodegradable time-release polymers, Surfactants, following; preservatives and thickening agents. Formulations of the present invention adapted for oral administration may con (a) any constituent chemical(s), Substance(s), agent(s) or tain a predetermined quantity of the active ingredient and plant extract(s) and mixtures thereof, that are capable of take the form of Sprays, liquids, Syrups, beverages, capsules, augmenting oxidative phosphorylation or mitochon powders, granules, Solutions, Suspensions, tablets, food, drial respiration, herein termed “OXPHOS (+)"; lozenges or any other form in which the active ingredients (b) any constituent chemical(s), Substance(s), agent(s) or are taken by mouth and absorbed through the alimentary plant extract(s) and mixtures thereof that can inhibit canal. Enteral formulations may also incorporate the active lactic acid dehydrogenase herein termed “LDH (-)"; ingredients with pharmaceutically acceptable carrierS Such as buffers, gums, Surfactants, fillers, preservatives, bulking (c) any constituent chemical(s), Substance(s), agent(s) or agents, colorants, diluents, flavoring agents, emulsifiers, plant extract(s) and mixtures thereof, that can inhibit Sugars, oils, cellulose, gelatin, flour, maltodextrose, time one or more of the following: malate Synthase, isoci release polymers and the like. trate lyase, phosphoenolpyruvate carboxylase/carbox ykinase, glycolate oxidase, phosphoglycolate phos 0.048. The term “therapeutically effective amount” is phatase, glycolaldehyde dehydrogenase, pyruvate defined as an amount of one or more of the active ingredients carboxylase, citrate lyase, aconitase, acetate-coA that comprise this invention, administered to an animal or ligase, ferridoxin oxidoreductase, fructose 1,6-bispho human at a dose Such that efficacy of the treatment can bring sphatase, 2,3-diphosphoglycerate mutase, propionyl about remission, prevention or halting of tumor growth or CoA carboxylase, malic enzyme, acetyl CoA carboxy any other desired clinical result. The formulation may be lase and ribulose-1,5-bisphosphate carboxylase, herein presented in unit dosage form and may be prepared by any termed anaerobic inhibiting component (AIC (-)), method well known in the art of pharmacy. The active wherein said AIC (-) can further comprise 2-3- ingredients of the formulation may be presented in liquid or dimethoxy-5-methyl-1,4 benzoquinone and/or Solid, in ampoules or vials (preferably amber) or pill form ubiquinones (5-45), wherein said 2-3-dimethoxy-5-me and can be further incorporated with a pharmaceutically thyl-1,4-benzoquinone and ubiquinones include chemi acceptable carrier, appropriate for the method of delivery as cal derivatives, analogs and mixtures thereof, and, deemed appropriate by one skilled in the art. (d) optionally, one or more chemotherapy drug(s) used for 0049. The formulation can be administered alone or in the treatment of cancer and/or a pharmaceutically combination to augment any chemotherapy agent(s) includ acceptable carrier. ing but not limited to: acetogenins, actinomycin D, adria 2. A composition of claim 1 wherein said OXPHOS (+) mycin, aminoglutethimide, asparaginase, bleomycin, bul further comprises any constituent (S) that can augment or latacin, buSulfan, carmustine, carboplatin, chlorambucil, contribute to the function of NADH:ubiquinone oxidoreduc cisplatin, cyclophosphamide, cytarabine, dacarbazine, tase (complex I), Succinate dehydrogenase-CoQ oxoreduc daunorubicin, doxorubicin, epirubicin, estradiol, etoposide, tase (complex II), ubiquinol:cytochrome c oxidoreductase fludarabine, flutamide, fluorouracil, floxuridine, gemcitab (complex III), cytochrome c oxidase (complex IV), ATP ine, glaucarubolone, hexamethylmelamine, hydroxyurea, Synthase (complex V) or mitochondrial respiratory function idarubicin, ifosfamide, interferon, irinotecan, leuprolide, either directly or indirectly Such as metabolic precursors or lomustine, mechlorethamine, melphalan, mercaptopurine, compounds required for the biosynthesis of coenzyme Q10, methotrexate, mitomycin, mitoZantrone, mitotane, Oxalipl Krebs cycle or respiratory enzymes or the function thereof; atin, pentostatin, plicamycin, procarbazine, quassinoids, and said LDH (-) can comprise any constituent (S) that are Simalikalactone, Steroids, Streptozocin, Semustine, tamox capable of inhibiting any relevant isoform of the LDH ifen, taxol, taxotere, tenipoSide, thioguanine, thiotepa, tomu enzyme, albeit preferably LDH-V, wherein said LDH can be deX, topotecan, treoSulfan, vinblastine, Vincristine, Vin derived from any relevant Source Such as plant, bacteria, desine and vinorelbine or mixtures thereof. yeast, mold, fungus, animal or tumor. US 2006/0035981 A1 Feb. 16, 2006
3. A composition according to claim 1, in which said eucalyptus and chemical constituents inherent to the afore OXPHOS (+) is further comprised of one or more selected mentioned and is present at about 0-100% wt of total from the group consisting of riboflavin, flavin mononucle composition. otide, flavin adenine dinucleotide, 5-amino-6-(5'-phosphor 10. A composition according to claim 9 further compris ibitylamino)uracil, 6,7-Dimethyl-8-(1-D-ribityl)lumazine, ing 2-3-dimethoxy-5-methyl-1,4-benzoquinone, ubiquinone ribitol, 5,6-dimethylbenzimidazole, pharmaceutically (s) (5-45), corresponding derivatives and analogues present acceptable Salts, precursors and derivatives of the Vitamin at about 30-80% wt of total composition, wherein said B2 molecule and ubiquinone (50); and said LDH (-) is OXPHOS (+) is present at about 15-30% wt of total com 2,3,4'5,7-pentahydroxyflavone or an analogous alternative. position and said LDH (-) is present at about 10-15% wt of 4. A composition according to claim 3, wherein Said total composition. analogous alternative further comprises one or more Selected 11. A composition according to claim 9, wherein Said from the group consisting of extract Solution(s) or Solids OXPHOS (+) is present at a concentration between 10 to derived from rosemary, myrrh, blackwalnut, Sage, nutmeg, 40% wt of total composition and said LDH (-) is present at ginger, clove, cinnamon, green tea, corriander, eucalyptus a concentration between about 60 to 90% wt of total and chemical constituents inherent to the aforementioned, a composition. polyphenolic compound, citric acid, epigallocatechin gallate 12. A method of preventing or treating cancer comprising and quercetin. administering to a patient in need, a therapeutically effective 5. A composition according to claim 1, wherein Said amount of one or more of the following; chemical derivatives further comprise Synthetic or natural derivatives of 2,3-dimethoxy-5-methyl-1,4-benzoquinone or (a) any constituent chemical(s), Substance(s), agent(s) or ubiquinones (5-45); and said analogs further comprise hyd plant extract(s) and mixtures thereof, that are capable of roquinones, ubichromenols (0-45), ubichromanols (0-45) augmenting oxidative phosphorylation or mitochon and ubiquinols (0-45). drial respiration, herein termed “OXPHOS (+)"; 6. A composition according to claim 2, wherein Said (b) any constituent chemical(s), Substance(s), agent(s) or precursors further comprise para-hydroxybenzoate, para plant extract(s) and mixtures thereof that can inhibit hydroxycinnamate or para-hydroxyphenylpyruvate, para lactic acid dehydrogenase herein termed “LDH (-)"; hydroxyphenylactate, polyprenyl-para-hydroxybenzoate, (c) any constituent chemical(s), Substance(s), agent(s) or tyrosine, phenylalanine and isopentyl-diphosphate or mix plant extract(s) and mixtures thereof, that can inhibit tures thereof; Said compounds further comprise tetrahydro one or more of the following: malate Synthase, isoci biopterin, vitamins B2, B6, B12, folate, niacin, vitamin C trate lyase, phosphoenolpyruvate carboxylase/carbox and pantothenic acid and mixtures thereof and Said ykinase, glycolate oxidase, phosphoglycolate phos OXPHOS (+) further comprises vitamin B1, lipoic acid and phatase, glycolaldehyde dehydrogenase, pyruvate biotin. carboxylase, citrate lyase, aconitase, acetate-coA 7. A composition according to claim 1, wherein Said ligase, ferridoxin oxidoreductase, fructose 1,6-bispho pharmaceutically acceptable carrier is further comprised of sphatase, 2,3-diphosphoglycerate mutase, propionyl Water, Saline, Starches, Sugars, gels, lipids, Waxes, glycerol, CoA carboxylase, malic enzyme, acetyl CoA carboxy Solvents, oils, liquids, proteins, glycols, electrolyte Solu lase and ribulose-1,5-bisphosphate carboxylase, herein tions, alcohols, fillers, binders, emulsifiers, humectants, pre termed anaerobic inhibiting component (AIC (-)), Servatives, buffers, colorants, emollients, foaming agents, wherein said AIC (-) can further comprise 2-3- Sweeteners, thickeners, Surfactants, additives and Solvents dimethoxy-5-methyl-1,4 benzoquinone and/or and mixtures thereof. ubiquinones (5-45), wherein said 2-3-dimethoxy-5-me 8. A composition according to claim 7, wherein Said thyl-1,4-benzoquinone and ubiquinones include chemi pharmaceutically acceptable carrier is made Suitable for cal derivatives, analogs and mixtures thereof, and, oral, injectable or external administration and further com prises the form of a Solid, liquid, powder, paste, gel, tablet, (d) optionally, one or more chemotherapy drug(s) used for granule, foam, pack, aerosol, Solvent, diluent, capsule, pill, the treatment of cancer and/or a pharmaceutically drink, liposome, Syrup, Solution, Suppository, emulsion, acceptable carrier. enema, Suspension, dispersion, food, bio-delivery agents 13. The method of claim 12 wherein said OXPHOS (+) and mixtures thereof. further comprises any constituent (S) that can augment or 9. A composition according to claim 1 further comprising contribute to the function of NADH:ubiquinone oxidoreduc one or more Selected from the group consisting of 2-3- tase (complex I), Succinate dehydrogenase-CoQ oxoreduc dimethoxy-5-methyl-1,4 benzoquinone, ubiquinone (s) tase (complex II), ubiquinol:cytochrome c oxidoreductase (5-45), corresponding derivatives and analogues present at (complex III), cytochrome c oxidase (complex IV), ATP about 0-100% wt of total composition, wherein said Synthase (complex V) or mitochondrial respiratory function OXPHOS (+) comprises one or more selected from the either directly or indirectly Such as metabolic precursors or group consisting of riboflavin, flavin mononucleotide, flavin compounds required for the biosynthesis of coenzyme Q10, adenine dinucleotide and derivatives of the vitamin B2 Krebs cycle or respiratory enzymes or the function thereof; molecule and ubiquinone (50) and is present at about and said LDH (-) can comprise any constituent (S) that are 0-100% wt of total composition and said LDH (-) further capable of inhibiting any isoform of the LDH enzyme, albeit comprises one or more Selected from the group consisting of preferably LDH-V, wherein said LDH can be derived from 2,3,4'5,7-pentahydroxyflavone, citric acid, a polyphenolic any relevant Source Such as plant, bacteria, yeast, mold, compound, epigallocatechin gallate, quercetin, eXtract Solu fungus, animal or tumor. tion(s) or Solids derived from rosemary, myrrh, blackwalnut, 14. The method of claim 12, in which said OXPHOS (+) green tea, Sage, nutmeg, clove, cinnamon, ginger, corriander, is further comprised of one or more Selected from the group US 2006/0035981 A1 Feb. 16, 2006
consisting of riboflavin, flavin mononucleotide, flavin riboflavin, flavin mononucleotide, flavin adenine dinucle adenine dinucleotide, 5-amino-6-(5'-phosphoribitylami otide and derivatives of the vitamin B2 molecule and no)uracil, 6,7-Dimethyl-8-(1-D-ribityl)lumazine, ribitol, ubiquinone (50) and is present at about 0-75% wt of total 5,6-dimethylbenzimidazole, pharmaceutically acceptable composition and said LDH (-) further comprises one or Salts, precursors and derivatives of the Vitamin B2 molecule more Selected from the group consisting of 2,3,4'5,7-pen and ubiquinone (50); and said LDH (-) is 2',3,4'5,7-pen tahydroxyflavone, citric acid, a polyphenolic compound, tahydroxyflavone or an analogous alternative. epigallocatechin gallate, quercetin, extract Solution(s) or 15. The method of claim 14, wherein said analogous Solids derived from rosemary, myrrh, blackwalnut, green alternative further comprises one or more Selected from the tea, Sage, nutmeg, clove, cinnamon, corriander, eucalyptus group consisting of extract Solution(s) or Solids derived from and chemical constituents inherent to the aforementioned rosemary, myrrh, blackwalnut, Sage, nutmeg, clove, cinna and is present at about 0-100% wt of total composition. mon, ginger, green tea, corriander, eucalyptus and chemical 21. The method of claim 20 further comprising 2-3- constituents inherent to the aforementioned, a polyphenolic dimethoxy-5-methyl-1,4 benzoquinone, ubiquinone (s) compound, epigallocatechin gallate, citrate and quercetin. (5-45), corresponding derivatives and analogues present at 16. The method of claim 12, wherein said chemical about 30-80% wt of total composition, where said OXPHOS derivatives further comprise Synthetic or natural derivatives (+) is present at about 15-30% wt of total composition and of 2,3-dimethoxy-5-methyl-1,4-benzoquinone or ubiquino said LDH (-) is present at about 10-15% wt of total nes (5-45); and said analogs further comprise hydroquino composition. nes, ubichromenols (0-45), ubichromanols (0-45) and 22. The method of claim 20, wherein said OXPHOS (+) ubiquinols (0-45). is present at a concentration between 10 to 40% wt of total 17. The method of claim 13, wherein said precursors composition and LDH (-) is present at a concentration further comprise para-hydroxybenzoate, para-hydroxycin between about 60 to 90% wt of total composition. namate or para-hydroxyphenylpyruvate, para-hydroxyphe 23. The method of claim 12, wherein said cancer further nylactate, polyprenyl-para-hydroxybenzoate, tyrosine, phe comprises one or more Selected from the group consisting of nylalanine and isopentyl-diphosphate or mixtures thereof; benign and malignant tumors of the skin, breast, colon, Said compounds further comprise tetrahydrobiopterin, Vita kidney, bone, blood, lymph, Stomach, gastrointestinal, mins B2, B6, B12, folate, niacin, vitamin C and pantothenic ovary, prostate, liver, lung, head and neck, gallbladder, acid and mixtures thereof and said OXPHOS (+) further adrenal, brain, central nervous System, bronchial, eye, hypo comprises Vitamin B 1, lipoic acid and biotin. thalamus, parathyroid, connective tissue, thyroid, pancreas, 18. The method of claim 12, wherein said pharmaceuti pituitary, nose, Sinus, mouth, endometrium, bladder, cervi cally acceptable carrier is further comprised of water, Saline, cal, bile duct, epithelial and Specific types Such as acute Starches, Sugars, gels, lipids, Waxes, glycerol, Solvents, oils, lymphoblastic leukemia, acute myeloid leukemia, AIDS liquids, proteins, glycols, electrolyte Solutions, alcohols, related cancers, Burkitt's lymphoma, astrocytomas/gliomas fillers, binders, emulsifiers, humectants, preservatives, buff and Hodgkin’s lymphoma. ers, colorants, emollients, foaming agents, Sweeteners, 24. The method of claim 12, wherein said chemotherapy thickeners, Surfactants, additives and Solvents and mixtures drug(s) further comprise one or more Selected from the thereof and Said administration further comprises one or group consisting of acetogenins, actinomycin D, adriamy more of the following routes: parental, oral, topical, intra cin, aminoglutethimide, asparaginase, bleomycin, bullata venous, intra-arterial, intra-tumor, intra-muscular, intra-peri cin, buSulfan, carmustine, carboplatin, chlorambucil, cispl toneal and Subcutaneous. atin, cyclophosphamide, cytarabine, dacarbazine, 19. The method of claim 18, wherein said pharmaceuti daunorubicin, doxorubicin, epirubicin, estradiol, etoposide, cally acceptable carrier is made Suitable for oral, injectable fludarabine, flutamide, fluorouracil, floxuridine, gemcitab or external administration and further comprises the form of ine, glaucarubolone, hexamethylmelamine, hydroxyurea, a Solid, liquid, powder, paste, gel, tablet, granule, foam, idarubicin, ifosfamide, interferon, irinotecan, leuprolide, pack, aeroSol, Solvent, diluent, capsule, pill, drink, liposome, lomustine, mechlorethamine, melphalan, mercaptopurine, Syrup, Solution, Suppository, emulsion, enema, Suspension, methotrexate, mitomycin, mitoZantrone, mitotane, Oxalipl dispersion, food, bio-delivery agents and mixtures thereof. atin, pentostatin, plicamycin, procarbazine, quassinoids, 20. The method of claim 12 further comprising one or Simalikalactone, Steroids, Streptozocin, Semustine, tamox more Selected from the group consisting of 2-3-dimethoxy ifen, taxol, taXotere, tenipoSide, thioguanine, thiotepa, tomu 5-methyl-1,4-benzoquinone, ubiquinone (S) (5-45), corre deX, topotecan, treoSulfan, vinblastine, Vincristine, Vin sponding derivatives and analogues present at about 0-100% desine and Vinorelbine. wt of total composition, wherein said OXPHOS (+) com prises one or more Selected from the group consisting of