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(12) Patent Application Publication (10) Pub. No.: US 2006/0035981 A1 Mazzio Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2006/0035981 A1 Mazzio Et Al 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.
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