International Journal of Medicine and Pharmaceutical Sciences (IJMPS) ISSN 2250 - 0049 Vol. 3, Issue 4, Oct 2013, 127-138 © TJPRC Pvt. Ltd.

POTENTIAL CLINICAL APPLICATIONS OF NATURAL PRODUCTS OF MEDICINAL AS ANTICANCER DRUGS – A REVIEW

RANJANI RAMAKRISHNAN Assistant Professor, Department of Virology, Sri Venkateswara University, Tirupati, Andhra Pradesh,

ABSTRACT

Cancer is a complex disease which is associated with cell signaling, DNA damage and cell cycle. Cancer is a multifactorial in origin .Cancer causes for 12.5% of deaths worldwide. Cancer treatment methods in cancer therapy like radiation and chemotherapy and using synthetic drugs leading to side effects. Therefore, there is a lot of demand to identify and develop effective novel therapeutic agents to treat many diseases. Plants are richest and unique source of energy, oxygen, metabolites and therapeutic agents. Many compounds of derivatives are very active against many dreadful diseases including cancer. Humans benefit from using many of the plants as medicinal purposes to combat diseases and microbes. Since plants are the natural, safe and best source in providing these active components especially anticancer drugs. Hence it is very essential to study about natural products and their potential role in therapeutic use.

This review paper focuses mainly on achievements in cancer therapy using plant products and the potential clinical applications of medicinal plants and the role of their products, especially as anticancer drugs.

KEYWORDS: Natural Products, Cytotoxic, Carcinoma, Lymphoma, Natural Products and Anticancer Drugs

INTRODUCTION

The major public health issue in world is cancer and one of the leading causes of death in the world (Hoyert et al., 2005). In Egypt, , India and Greece people have been used plants and natural products for the treatment of various diseases from ancient time. Nearly 80 % of the world’s population depends on traditional medicine (Farnsworth et al., 1985; Mohammad Shoed, 2006). The phytochemicals such as flavonoids, alkaloids and tannins are isolated from Indigofera aspalathoides (Compositae) and the flavavonoids have antimutagenic, antimalignant and chemopreventive activity and Wedelia calendulaceae compounds inhibit Lipoxigenases (Lox) and caspases and Lox inhibitor act as anticancer activity (Malaya Gupta et al., 2007). Tecoma stans exhibit good anticancer activity. Three trifoliate plants like Glycine max, cajanus cajan and Phaseolus vulgaris are screened for anticancer plants by Pranay Dogra (2009). More than 60% of anticancer drugs are in clinical use are derivatives of natural sources (Cragg and Newman, 2005; 2004/Rev.2006). The organic extracts of leonurus on many cell lines showed cytotoxic effect (Nalise Low Ahkee et al., 2008). Rajdeep kaur at al., (2011) made an attempt to review on different types of plant sources and their role in prevention and treatment of cancer. The novel anticancer agents from tropical rainforest plants are described by Douglas Kinghorn et al., (1999). There are nine anticancer drugs clinically approved for use and they are vinblastine, Vincrintine, navelbine, Etoposide, Teniposide, Taxol, Taxotere, topotecan and Irinotecan (Hui – kang and Kuo- Hsiung Lee, 1997). Joy et al (2001) made an attempt to listout the important medicinal plants with active principles against various diseases including cancer.

The supplement of Spirulina prevents cancer due to presence of some active compounds which act as antioxidant and immunomodulator causing tumor destruction. (Karkos et al., 2008). The major constituents, thymoquinone and β – elemene of Nigella Sp. are potential chemotherapeutic and chemopreventive anticancer agents (Amr E. Edris, 2009). 128 Ranjani Ramakrishnan

The extract of Typhonium divaricatum has anticancer property against nine human cancer cell lines but this can not be recommended as a primary treatment for cancer (NeoH, 1996). The whole plant extract of Argemone mericana showed in-ivitro cytotoxic effect on cell line (Satish kumar verma et al., 2010). Plant produced therapeutic HPV 16 E7 vaccine eliminates tumors in animal models and induce specific cell mediated immune responses in early phases of human trials (Silvia Massa et al., 2007).

The essential oils extracted from leaf of Croton flavens showed cytotoxic effect on cell line (Muriel sylvestre et al., 2006). Inhibition of DNA replication by comptothecin was studied Pantazis et al., (1996); Vineesh et al., (2007). The web based databases of phytochemicals with anticancer properties of Indian medicinal plants are provided by Umashankar vetrivel et al., (2009). The plants and also some microbial organisms produce some antibiotics with antitumor activity such as bleomycin, dactinomycin, mitomycin C and anthracyclines Douglas Kinghorn, et al., (2009). The anticancer properties of Goniothalamus ubrosus (Kerenak) (Lee et al., 2003), Antiproliferative properties of Gynura procumbens (sambung nyawa) (Lee et al., 2007), antitumor activity of Kaempferia galangal (Cekur) (Kirana et al.,2003), Morinda citrifollia (Mengkudu) (Wang and Su, 2002), lawsonia inermis is an anticarcinogenic, antioxidant ( Endrini et al., 2002), Baringtonia racemosa (Putut kanpung) (Thomas et al., 2002; Siddig Ibrahim Abdel- Waheb (2009), The anticancer properties of Allium sativum, reviewed (Ranjani, and Ayyaraju, 2012). The water extract of Myrmecodya pendens , is an Indonesian traditional medicine and belongs to Rubiaceae family (Soeksmanto et al., 2010). Indole alkaloids of Tabernaemontana divaricata displayed in- vitro cytotoxic against human cancer cell lines (Mei-Fen Bao et al., 2013).

The Anticancer Compounds Identified from Plants

The phytochemicals showed potential effect on prevention of cancer and in chemotherapy. Several plant products such as alkaloids, lignans, saponins, tannins, flavonoids, terpenes, taxanes, vitamins, minerals, biomolecules and other primary and secondary metabolites play vital role in treatment of tremendous diseases including cancers. These compounds are having versatile therapeutic functions such as antimicrobial, antibacterial, antiviral, antioxidant, immunomodulatory property and also act as anticancer, antitumor, antimitotic or antiproliferative, antiangiogenic, inhibitors of enzymes of cell differentiation and cell cycle progression.

Table 1: Anticancer Properties of Natural Compounds of Medicinal Plants Family Belongs Compound S. No Plant Name Name of the Compound to Category Podophyllum peltatum Linnaeus, 1 Podophyllaceae Lignin: podophyllotoxin Podophyllum emodii Vinca alkaloids, vinblastine 2 Catharanthus roseus G. Don Apo-cynaceae Alkaloids: (VCR) and vincristine (VLB) Camptothecin (CPT) and 10 3 Capmtotheca acuminate Decne Nyssadeace Alkaloids: – Hydroxycamptothecin (OPT) Harringtonine and 4 Cephalotaxus harringtonia Var. drupacea cephalotaxaceace Alkaloids: isoharringtonine 5 Colchicum autumnale Colchicaceae Alkaloids: Colchicine Bleekeria vitensis Apocynaceae Alkaloids: Elliptinium 7 Coptidis Rhizoma (Huanglian) Ranunculaceae Alkaloids: Berberine 8 Combretum caffrum Combretaeae Phenols: Combretastatins Betula Sp Betula Sp; mauritiana, Ziziphus (Betulaceae) and 9 Triterpinoids: Betulinic acid rugosa and Ziziphus oenoplia Ziziphus Sp. () 10 Taxus brevifolia Taxaceae Terpenes: Taxol (Paclitaxel) Potential Clinical Applications of Natural Products of Medicinal Plants as Anticancer Drugs – A Review 129

Table 1: Contd., Terpenes, 11 Hippophae rhamnoides, (Sea Buckthorn) Elaeagnaceae Carotenoids, polyphenols phenols 12 Cymbopogon flexuosus (Lemon grass ) Poacae essential oil: essential oil 13 Triticum aestivum (wheat grass) Poacae Oil: Oil and alkaloids 14 Ricinus communis Euphorbiaceae Protein: Ricin Indigo naturalis (Quing - Dai), Baphica canthus, Indigo tinctoria , Polygonum 15 compositae Flavonoids: Indurubin tingctorium or Isatis tinctoris, Indigo aspalathiodes Indole Cononitarine B and 16 Tabernaemontana divaricata Apocynaceae akaloids conophylline

Podophyllotoxins –Lignans and its Analogs

The Podophyllin is an antimitotic compound and discovered in 1946. The American mandrake or Mayapple, podophyllum peltatum Linnaeus is used by the Penobscot Native Americans of Maine in 1940 and Indian subcontinent Podophyllum emodii Wallich belongs to Podophyllaceae have medicinal importance from ancient days and used in the treatment of skin cancer and warts. In 1940, the topical application of Podophyllin an alcohol extract of the dried roots of P.peltatum has proved that cured veneral warts. The important lignin, podophyllotoxin is isolated in 1880 and its structure reported in 1950s and its isomer is isopodophyllotoxin has high level of toxicity (Hartwell and Schrecker 1959). In Switzerland 1960 and 1970, Sandoz laboratories developed two active anticancer analogs which are etoposide (VP 16 or VP 16-213) and teniposide (VM 26) are synthesized in 1965 and commercialized in 1976 as Vumon® and Vehim ®. In 1983 etoposide which was approved by U.S. FDA for treating testicular cancer and introduced in US market as Vepesid® and is one of the most active anticancer agents in the treatment of testicular teratoma, Hodgkin’s and non-Hodgkin’s lymphomas, SCLC and a variety of malignant cancers. There are three etoposide derivatives which are etoposide phosphate (BMY- 40481: Schacter et al., 1994; Sessa et al., 1995, Wang and Lee 2001; Cragg and Newmann, 2005, 2004/2006). NK 611 [4- demethylepipodophyllotoxin -9 (2-deoxy-2 dimethylamino -4, 6-o- ethylidene) - β- D-glucopyranoside ] in Tokyo, Japan and was developed by Nippon Kayaku. It is a water soluble derivative with potent anti-neaoplastic activity (Machida et al., 1993.). GL331 is a novel to topoisomerase II inhibitor in both in vivo and in vitro and it is a derivative of epipodophyllotoxin. It was originally discovered as anticancer agent, developed and licenced to Genelabs, Inc., , USA in 1993 (Wang and Lee., 1997). Etoposide and teniposide are clinically active against lymphomas and bronchial and testicular cancers. Due to lack of efficacy and high toxicity many of the podophyllotoxin like lignans were identified but to be dropped (Cragg and Newmann, 2005, 2004/2006; Shoeb, 2006, Rajandeep Kaur et al., 2011).

Vinca Alkaloid and its Analogs

Vinca alkaloids, vinblastine (VCR) and vincristine (VLB) and its semisynthetic derivatives isolated from Catharanthus roseus G. Don. (Apo-cynaceae), commonly known as Madagascar periwinkle. and vinblastine and vincristine its semisynthetic derivatives are used in the United States (US) and other countries against a variety of cancers. (Wang and Lee, 1997; Cragg and Newmannn, 2004/Rev.2006; Mahammed Shoeb, 2006; Madhuri and pandey, 2009;; Badri Nagarani et al., 2011; Rajandeep Kaur, 2011). Vincristine is used in treatment of leukemias, breast and lung, lymphoma, advanced testicular cancer, Kaposi’s sarcoma and hepatocellular carcinoma. Vinblastine is active against non- small cell lung carcinoma (NSCLC) and advanced breast cancer (Wang and Lee, 1997; Cragg and Newmannn, 2004/Rev.2006). Vinfosiltine (S12363) is a vinca alkaloid derivative, semisynthetic analog has effect on advanced malignant melanoma (Stanley et al., 1993) and advanced breast cancer (Adenis et al., 1995). Another semisynhtetic 130 Ranjani Ramakrishnan analog of vinblastine known as vinovelbine (5' – noranhydrovinblastine) is approved by USFDA (as NAvelbine/ Welcome) for the treatment of advanced non-small cell lung carcinoma –NSCLC in 1995(Crawford, 1996) and in breast cancer (Gao and Faulds, 1994).

Camptotheca Alkaloids

Camptothecin is a potent DNA topoisomerase I inhibitor isolated from Capmtotheca acuminate Decne (Nyssadeace) is a Chinese ornamental tree popularly known as tree of Joy possesses potent anticancer property. Campotheca products Camptothecin (CPT) and 10 – Hydroxycamptothecin (OPT) were primarily isolated from the wood, fruits and bark and clinical trial made by National Cancer Institute (NCI) in 1990(Wall et al., 1996). Sodium camptothecin is used in the treatment of gastric carcinoma, rectal, colon, bladder and other malignancies in the United States in 1970s. Later it was stahled because of its severe side effect causing bladder toxicity. The OPT (10 – Hydroxycamptothecin) is effective on different types of cancers like head, neck, gastric carcinoma and primary liver carcinoma with less adverse effects than Sodium camptothecin. (Hsu, 1980; Wang and Lee., 1997). The structural and functional studies support that camptothecin and its derivatives inhibit the functions of DNA topoisomerase I activity and thus acts as cytotoxic compounds (Jaxel et al., 1989, Hertzberg et al., 1989; Hsiang et al.,1989; Kingsbury et al., 1991). Camptothecin analogues, 9- amino camptothecin acts as anticancer agent, topotecan (Hycamptin) acts against ovarian cancers and non-small cell lung carcinoma and Irinotecan (CPT 11) (Japan) is effective against colon cancers. (Wang and Lee, 1997; Cragg and Newmann, 2004/2006; Rajandeep Kaur et al., 2011; Badri Nagarani et al., 2011).

Cephalotaxus Alkaloids

Cephalotaxus alkaloids are protein synthesis inhibitors have effect on molecular events involved in the synthesis of protein such as initiation of protein synthesis, release of nascent peptide or protein chains, polyribosome degradation but not on elongation of new peptide chain. (Haung, 1995; Smith et al., 1976; Wang and Lee., 1997). Cephalotaxus harringtonia Var. drupacea (Sieb and Zucc) belongs to cephalotaxaceace is a chines tree and harringtonine and isoharringtonine are cephalotaxus alkaloids are in clinical use as anticancer agent. Homoharringtonine in tested in the treatment of acute myelogenous leukemia (AML) patients (Fieldman et al., 1992a, tested in advanced breast cancer (Zhao et al., 1986) used in myelodysplastic syndrome and chronic myelogenous leukemia (CML) (Fieldman et al., 1996; Cragg and Newmann, 2006; Rajandeep Kaur et al., 2011). The pure homoharringtonine (HHT) is effective on various leukemias. In China harringtonine and in combination with HHT used successfully in the treatment of AML and CML (Wang and Lee., 1997; Cragg and Newmann, 2004/2006).

Colchicine Alkaloids

A classical drug colchicines and its analogs identified from Colchicum autumnale and belogs to Colchicaceae family. They are antimitotic, tubulin binding action and antitumor agent (Zweig and Chignell, 1973; Lee et al., 1994) has high toxicity. A semisynthetic derivative called colchicinamide shows a potent antitumor activity against different types of solid tumor also in the treatment of breast cancer in China (Hsu, 1980). Another semisynthetic derivative called deacetylcolchicine is very effective against melanoma, Hodgkin’s lymphoma and chronic granulocytic leukemia (Yashikuni and Bross, 1988; Wang and Lee, 1997). According to recent in-vitro studies, deacetamidothiocolchicine 7 –ols and its esters are developed from colchicines shows potent inhibition against tubulin polymerization and selective cytotoxicities against colon, melanoma and CNS cancers.

Potential Clinical Applications of Natural Products of Medicinal Plants as Anticancer Drugs – A Review 131

Ellipticine Alkaloids and Analogs

Ellipticine is topoisomerase II inhibitor and antitumor alkaloids of Bleekeria vitensis. Fijian medicinal plant with potent anticancer property belongs to Apocyanaceae family. (Suffness and Douros et al., 1980); Ochrosia elliptica (Goodwin et al., 1959); O.acuminata (Lin et al.,1985). Ellipticine analogs are N-2- (Diethylaminoethyl) – 9 – hydroxyellipticinium chloride (DHE)is used for the treatment of breast cancers in Euope (Rouess et al., 1993); 2-N-methyl 9-hydroxyellipticine (NMHEs) used against metastatic breast cancer (Rouess et al., 1981) and SR 95325 B (Retelliptine dihydrochloride, NSC D-626717 - W) is having a very high level of antitumor activity against solid tumors in resistance murine models (Kattan et al., 1994; wang and Lee, 1997). A derivative of elipticine known as elliptinium is in clinical use in France for the treatment of the breast cancer (Wang and Lee, 1997; Cragg and Newmann, 2005, 2004/2006; Shoeb, 2006, Rajandeep Kaur et al., 2011). .

Berberine - Isoquinoline Alkaloid

Berberine is a product of isoquinoline alkaloid isolated from Coptidis Rhizoma (Huanglian) belongs to Ranunculaceae family. which is a Chinese medicinal herb with antiproliferative, anticancer properties both in in vitro and in vivo and is protoberberine alkaloids. It inhibits tumerigenic Helicobacter pylori and Hepatitis B Viruses, regulations of some oncogene and carcinogenesis and interaction with nucleic acids both DNA and RNA. (Sharma et al., 2011, Badri Nagarani et al., 2011).

Combretastatins and Analogs (Phenols)

The combretastatins of stilbeneare an anti-angiogenic agents isolated from Combretum caffrum (ECKl Zey b) Kunze (Combretaeae) collected in in 1970 fro NCI. In view of development of novel anticancer agents. NCI collaborated with botanical Research Institute of South Africa, isolated combretastatins and developed many of its derivatives. Combretastatinn belongs to family of stilbenes which act against tumor and causes tumor necrosis due to antiangiogenic property. Combretastatins A-4 CA4) is a water soluble analog and its mimics are in clinical trial and is effective against leukemia, colon and lung cancers (Ohsumi et al., 1998; Pettit et al., 1995; Shoeb, 2006; Li and Sham, 2002; Cragg and Newmann, 2005, 2004/2006; Rajandeep Kaur et al., 2011). The Indian medicinal tree Terminalia bellerica belongs to combretaceae family and its bark, kernel and fruit are used in isolation of active compounds with anticancer properties (Joy et al., 2001; Cragg and Newmann, 2005, 2004/2006; Shoeb, 2006, Rajandeep Kaur et al., 2011).

Triterpenoid Acids

Triterpenoid acids like oleanolic and ursolic acid are anticancer activities and is associated with anti- inflammatoryproperty. The potent in vivo and in vitro antitumor activity against a breast carcinomas, pancreatic carcinomas and leukemias and is a CDDO (2-cyano -3, 12- dioxoolean1, 9- dien-28-oic acid) and its methyl ester; CDDO is active against epithelial ovarian carcinoma (EOC) and EOC is one of the leading cause of death (Couch et al., 2005; Cragg and Newmann, 2005; Melichar et al., 2004).

Betulinic acid is a phytochemical, lupine type triterpene isolated from Betula Sp (Betulaceae) and Ziziphus Sp. (Rhamnaceae) are cytotoxic against a range of cancer cell lines including human melanoma cell line in association with NCI. It has many other biological activities such as antibacterial, anti-inflammatory, antiviral and antimalarial agents. Ziziphus species such as Ziziphus mauritiana, Ziziphus rugosa and Ziziphus oenoplia are source of betulic acid.

Taxol-Terpenes

The acific yew tree, Taxus brevifolia belongs to taxaceae is an endangered species (Wani et al., 1971). A highly 132 Ranjani Ramakrishnan active chemotherapeutic diterpene, Taxol (Paclitaxel) was isolated from bark of Taxus Sp.s collected in Washington state by U.S. Department of Agriculture (USDA), active against ovarian, NSCLC and breast cancers. The leaves of Taxus baccata (contains baccatin III) is a traditional Asiac Indian (Ayurvedic) medicine and used as anticancer agent and taxols analog is docetaxel (Taxotere ®) is used in the treatment of NSCLC lung and breast cancer has geater cytotoxic effect (Hanaus Ke et al., 1992; Cragg and Newmann, 2005,2004/2006). The Taxuchin A identified from the Taxus Chinensis, bark and the leaves and stems of Taxus yunnanensis containing Yunantaxusin (Zhang et al., 1994a and 1994b) are the new taxoids. Docetaxel is highly toxicto patients than taxol. Taxol promotes polymerization of tubulin, stabilizes the structure intracellular microtubules (Wang and Lee., 1997; Cragg and Newmann, 2005, 2004/2006; Shoeb, 2006, Rajandeep Kaur et al., 2011).

Sea-Buckthorn

Hippophae rhamnoides, (Elaeagnaceae) contains very high amounts of antioxidant called carotenoids. Sea Buckthorn prevents growth of cancer due to presence of high amounts of antioxidants called carotenoids and high vitamin E and also potent anticancer natural sources.

Lemon Grass Essential Oil

The studies indicate that lemon grass essential oil with its potential, inexpensive and alternative treatment (Koganov et al., 1999). Lemon grass oil form Cymbopogon flexuosus belongs to Poacae family with anticancer properties.

Wheat Grass

Wheat grass is a wholesome food and the king alkaloid foods high in alkalinity, helps fight acidity, also Triticum aestivum (wheat) belongs to Poacae family. It is known as green blood increases production of hemoglobin that kills cancer. Wheat grass helps to prevent cancer by balancing pH to its required pH (Bijal Patel et al., 2010).

Ricin – Protein

Ricin is a phytoprotein toxin isolated from Ricinus communis (Tavansolian and Kharrazy, 1978). The Ricin contains two polypeptide chains A and B linked by a disulphide bond and their molecular weight is 30kda and 32 kda respectively. It inactivates the 60S ribosomal subunit and thus, terminates protein synthesis. Monoclonal antibody- ricin A chains have been conducted for the treatment of metastatic melanoma, colon cancer and B-cell lymphoma in U.S. (Selvaggi et al., 1993; Lo Russo et al., 1995; Sansville, 1995; Wang and Lee 2001).

Flavones/ Flavonoids

Approximately 4000 distictive flavonoids are isolated from fruits, vegetables and other plant food reduce the risk of cancer and other chronic diseases. Flavonoids will also inhibit DNA topoisomerase – I, COX- I (cycloxigenase). The chemopreventive agents delay or reverses at multiple sites of carcinogenesis by blocking effect or suppressing effect (Badri Nagarani et al., 2011). Several flavanoids with cytotoxic antitumor agent, reviewed by Wang et al., 1996).

Flavone-8- acetic acid (FAA, NSC 347512) is a synthetic derivative of the basic flavonoid skeleton with preclinical activity. Studies on FAA in U.S. (Holmund et al., 1995), France (de Forni et al ., 1995), Newzealand (Thomson et al., 1992), UK (O’ Reilly et al., 1993; Wang and Lee 1997). FAA induces synthesis of nitric oxide, a physiological mediator and potential cytotoxic agent.

Indurin – Bis Indoles and its Analogs

Indurin and its analogs are the inhibitors of cyclin dependent kinases (Cdks) and Cdks are vital cell cycle Potential Clinical Applications of Natural Products of Medicinal Plants as Anticancer Drugs – A Review 133 regulatory protein. The Chinese medicinal plant Indigo naturalis (Quing - Dai), leaves of Baphica canthus (with blue pigment), Indigo tinctoria , Polygonum tingctorium or Isatis tinctoris are the natural sources of Indurubin (Xiao, 1981) and Indigo aspalathiodes (Malaya Gupta et al., 2007) belongs to compositae family is containing flavonoids with antimutagenic , antimalignant and chemopreventive properties. Indurubin and its derivative N- methyl indurubin oxime is in clinical use for treatment of CML (Ma et al., 1980); Wang and Lee., 1997). Indigo tinctoria (Mu Lan; Leguminaceae) is source of indurubin used to treat CML and is a product of isatin and indoxylindole derived molecules found in indigo producing plants, gastropod mollusks (Tyrian purple) .

ACKNOWLEDGEMENTS

This research work was supported by the UGC Major Research Project File No: 39-224/2010(SR). We thank to BADRI KAMESHWAR RAO, USA, Prof. D.V.R. Sai Gopal, Head & BOS, Department of Virology, S.V.University and Prof. S.D.S. Murthy, Head, Department of Biochemistry, S.V.University, Tirupati, AP, India.

Note: I thank all the authors quoted in this article for their contribution and their research and NCI, USA.

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