Natural sources as potential anti-cancer agents: A review

International Journal of Phytomedicine 3 (2011) 09-26 http://www.arjournals.org/index.php/ijpm/index Review ISSN: 0975-0185 Natural sources as potential anti-cancer agents: A review Abhishek Bhanot, Rohini Sharma, Malleshappa N. Noolvi* *Corresponding author: Malleshappa N. Noolvi Department of Natural Chemistry, ASBASJSM College of Pharmacy, Bela, Ropar, Punjab (India)140111 E-mail: mnoolvi@yahoo.co.uk Bhanot abhi82bhanot@gmail.com Mo. No: +91 9417563874 +91 9878371275 Fax: +91 1881 263655. Abstract Natural products remain an important source of new drugs, new drug leads and new chemical entities. The plant based drug discovery resulted mainly in the development of anticancer agents including plants (vincristine, vinblastine, etoposide, paclitaxel, camptothecin, topotecan and irinotecan), marine organisms (citarabine, aplidine and dolastatin 10) and micro-organisms (dactinomycin, bleomycin and doxorubicin). Beside this there is numerous agents identified from fruits and vegetables can used in anticancer therapy. The agents include curcumin (turmeric), resveratrol (red grapes, peanuts and berries), genistein (soybean), diallyl sulfide (allium), S-allyl cysteine (allium), allicin (garlic), lycopene (tomato), capsaicin (red chilli), diosgenin (fenugreek), 6-gingerol (ginger), ellagic acid (pomegranate), ursolic acid (apple, pears, prunes), silymarin (milk thistle), anethol (anise, camphor, and fennel), catechins (green tea), eugenol (cloves), indole-3-carbinol (cruciferous vegetables), limonene (citrus fruits), beta carotene (carrots), and dietary fiber. In this review active principle derived from natural products are offering a great opportunity to evaluate not only totally new chemical classes of anticancer agents, but also novel lead compound and potentially relevant mechanisms of action. Keywords: Cancer, vincristin, vinblastin, fruit, vegetables. Introduction Cancer continues to be one of the major causes of death worldwide and only modest progress has been made in reducing the morbidity and mortality of this disease [1]. Cancers may be caused in one of three ways, namely incorrect diet, genetic predisposition, and via the environment. As many as 95% of all cancers are caused by life style and may take as long as 20– 30 years to develop. Current estimates from the American Cancer Society and from the International Union Against Cancer indicate that 12 million cases of cancer were diagnosed last year, with 7 million deaths worldwide; these numbers are expected to double by 2030 (27 million cases with 17 million deaths) [2]. According to a report of World Health Organization, more than 80% of world’s populations depend on traditional medicine for their primary health care needs [3,4]. Plants have a long history of use in the treatment of cancer and it is significant that over 60% of currently used anti-cancer agents are come from natural sources [5]. Naturally occurring drugs that are part of the war against cancer include vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine), taxanes (paclitaxel, docetaxel), podophyllotoxin and its derivative (etoposide, teniposide), camptothecin and its derivatives (topothecan, irinothecan), anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) and others. In fact, half This work is licensed under a Creat ive Com m ons At t ribut ion 3.0 License. Bhanot et al. International Journal of Phytomedicine 3 (2011) 09-26 the wild chervil Podophyllum emodi [14]. It has also significant activity against small-cell lung carcinoma [15]. Etoposide is a topoisomerase II inhibitor, stabilizing enzyme–DNA cleavable complexes leading to DNA breaks [16]. The taxanes paclitaxel and docetaxel has been show antitumor activity against breast, ovarian and other tumor types in the clinic trial. Paclitaxel stabilizes microtubules and leading to mitotic arrest [17]. In addition, the camptothecin derivatives irinotecan and topotecan, have shown significant antitumor activity against colorectal and ovarian cancer respectively [18,19]. These compounds were initially obtained from the bark and wood of Nyssacea Camptotheca accuminata and act by inhibiting topoisomerase I [20]. The taxanes and the camptothecins are presently approved for human use in various countries (Table 1). of all anti-cancer drugs approved internationally were either natural products or their derivatives and were developed on the basis of knowledge gained from small molecules or macromolecules that exist in nature [6,7]. In between 2001 and 2005, 23 new drugs derived from natural products were introduced for the treatment of disorders such as bacterial and fungal infections, cancer, diabetes, dyslipidemia, atopic dermatitis, Alzheimer’s disease and genetic diseases such as tyrosinaemia and Gaucher disease out of these 4 drugs have been approved as anti cancer agents. The approved anti cancer agents in 2002 doxorubicin, in 2002 estradiol, in 2004 cholorophyll and l- aspartic acid and taxol nanoparticles in 2005 [8]. Three new drugs also introduced in 2007 originate from microbial sources for the treatment of cancer is marine alkaloid trabectedin, epothilone derivative ixabepilone and temsirolimus [9]. Table 1: Plant based anticancer agents in clinical practice. Nature is an attractive source of new therapeutic candidate compounds as a tremendous chemical diversity is found in millions of species of plants, animals, marine organisms and microorganisms as potential anti-cancer agent [10,11]. In this present study the potential anticancer agent from plants, marines, microorganisms and dietary (fruits, vegetables, and spices) sources with some recent advancement in the field of cancer research were discussed. S.No. Compound Uses Status 1. Vincristine Leukemia, lymphoma, Phase breast, lung, pediatric III/IV solid cancers and others 2. Vinblastine Breast, lymphoma, Phase germ-cell and renal III/IV cancer 3. Paclitaxel Ovary, breast, lung, Phase bladder and head and III/IV neck cancer 4. Docetaxel Breast and lung cancer Phase III 5. Topotecan Ovarian, lung and Phase II/III pediatric cancer 6. Irinotecan Colorectal and lung Phase cancer II/III Rohitukine the plant alkaloid, isolated from the leaves and stems of Dysoxylum binectariferum (Maliaceae) [21,22]. Synthetic flavone derived from rohitukine, Flavopiridol representing the first cyclin-dependent kinase inhibitor to enter the clinical trial [23]. The mechanism of action involves interfering with the phosphorylation of cyclin-dependent kinases and arrest cell-cycle progression at growth phase G1 or G2 [24,25]. Plants as source of anti-cancer agents: The history of plant as source of anti-cancer agents started in earnest in the 1950s with the discovery and development of the vinca alkaloids (vinblastine and vincristine) and the isolation of the cytotoxic podophyllotoxins. Vinca alkaloid was responsible for an increase in the cure rates for Hodgkin’s disease and some forms of leukemia [12]. Vincristine inhibits microtubule assembly, inducing tubulin selfassociation into coiled spiral aggregates [13]. Etoposide is a epipodophyllotoxin, derived from the mandrake plant Podophyllum peltatum and 10 Bhanot et al. International Journal of Phytomedicine 3 (2011) 09-26 Homoharringtonine an alkaloid isolated from the Chinese tree Cephalotaxus harringtonia (Cephalotaxacea) [26]. The mechanism of action is the inhibition of protein synthesis and blocking cell-cycle progression [27]. It has shown efficacy against various leukemias [28]. A lung-cancer-specific antineoplastic agent 4Ipomeanol is isolated from the sweet potato Ipomoea batata (Convolvulaceae) [29]. The mechanism of action is converted into DNAbinding metabolites upon metabolic activation by cytochrome P450 enzymes that are present in cells of the lung [30]. DNA topoisomerase I inhibitor β-lapachone, that induces cell-cycle delay at G1 or S (synthesis) phase before inducing either apoptotic or necrotic cell death in a variety of human carcinoma cells, including ovary, colon, lung, prostate and breast [31]. Beside this there are so many plants which are used in cancer; following enlist the plant which prevent and target for future studies as potential anticancer agent (Table 2): Table 2: Plants used as anti-cancer. S.No 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. Plant Species Salvia officinalis Viscum album Combretum caffrum Melaleuca alternifolia Lavandula angustifolia Aglaia foveolata Maytenus serrata Tabebuia impetiginosa Tabebuia rosea Tabebuia serratifolia Dipteryx odorata Thapsia garganica Indigofera tinctoria Matricaria chamomilla Erythroxylum pervillei Broussonetia papyrifera Cyclopia intermedia Scutellariae radix, Scutellariae indica Physalis philadelphica Dysoxylum binectariferum Aristotelia chilensis Cyathostemma argentium Epimedium hunanense Croton urucurama Epilobium hirsutum Pleione bulbocodioides Cassia quinquangulata Begonia glabra Celastrus orbiculatus Croton draco Smilax sieboldii Ximenia Americana Family Labiatae Loranthaceae Combretaceae Myrtaceae Labiatae Meliaceae Celastraceae Bignoniaceae Bignoniaceae Bignoniaceae Fabaceae Apiaceae Leguminosae Asteraceae Erythroxylaceae Urticaceae Fabaceae Labiatae Solanaceae Meliaceae Elaeocarpaceae Annonaceae Berberidaceae Euphorbiacaeae Onagraceae Orchidaceae Caesalpiniaceae Begoniaceae Celastraceae Euphorbiacaeae Liliaceae Olacaceae 11 Plant Part Leaves Leaves Bark Leaves Leaves Fruit Seed Stem bark and trunk wood Stem bark and trunk wood Stem bark and trunk wood Seed Fruit Aerial part Flower Root Entire Leaves Root Seed Stem bark Leaf and Stem Root Aerial parts Bark Entire Tuber Root Entire Entire Aerial parts Entire Root References [32] [33] [34] [35] [35] [36] [37] [38,39] [38,39] [38,39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [57] [57] [58] [58] Bhanot et al. International Journal of Phytomedicine 3 (2011) 09-26 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43 44. 45. 46. 47. 48. 49 50. 51. 52. 53. 54 55. 56. 57. 58. 59. 60. 61. 62. 63. 64 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. Maytenus emarginata Sarcandra glabra Salvia plebeian Scutellaria barbata Ocotea caparrapi Caragana cuneata Croton flavens Euphorbia heterophylla Echites vucatanensis Thevetia ahouia Thevetia gaumeri Thevetia peruciana Euphorbia ebracteolata Dioscorea collettii Juglans mandshurica Maackia tenuifolia Juncus acutus Hedyotis chrysotricha Arisaema erubescens Leptadenia hastate Viscum calcaratum Aphanamixis polystachya Pratia nummularia Aeonium arboretum Ocotea foetens Maytenus canariensis Sedum alboroseum Euphorbia micractina Euphorbia prolifera Scirpus holoschoenus Dillenia suffruticosa Hypoxis rooperii Inula linariaefolia Ziziphus mauritiana Adiantum macrophyllum Thalictrum fabri Scutellaria indica Hypericum japonicum Cyathea fauriei Fissistigma oldhamii Monnina obtusifolia Coriolus versicolor Melastoma malabathricum Carapa guianensis Swietenia humilis Ficus pretoiae Celastraceae Choranthaceae Labiatae Labiatae Lauraceae Leguminosae Euphorbiacaeae Euphorbiacaeae Apocynaceae Apocynaceae Apocynaceae Apocynaceae Euphorbiacaeae Dioscoreaceae Juglandaceae Leguminosae Juncaceae Rubiaceae Araceae Asclepiadaceae Loranthaceae Meliaceae Campanulaceae Crassulaceae Lauraceae Celastraceae Crassulaceae Euphorbiacaeae Euphorbiacaeae Cyperaceae Dilleniaceae Hypoxiaceae Compositae Rhamnaceae Pteridaceae Ranunculaceae Labiatae Guttiferae Cyatheaceae Annonaceae Polygalaceae Polyporaceae Melatomataceae Meliaceae Meliaceae Moraceae 12 Entire Entire Aerial Entire Essential oil Leaf Leaf Stem Latex Leaf and Stem Leaf and Stem Leaf and Stem Aerial parts Rhizome Root Root Leaf Entire Root Bark Entire Stembark Entire Leaf Branchlets Fruit juice Entire Entire Latex Inflorescence Fruit Tuber Flowers Stem bark and Fruit Entire Root Root Entire Shoot Stem Aerial parts Fruitbody Flower Seed oil Seed Sap [59] [60] [61] [62] [63] [64] [65] [65] [65] [65] [65] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] Bhanot et al. International Journal of Phytomedicine 3 (2011) 09-26 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. Croton lechleri Aster amellus Crassocephalum bojeri Echinops grijisii Adenium obesum Ipomea batata Uncaria tomentosa Plantago asiatica Phymatosorus diversifolium Rabdosia rubescens Salvia chinensis Ganoderma lucidum Euphorbia kansui Echinops latifolius Euphorbia marginata Ligustrum lucidum Phytolacca esculenta Pinus parviflora Dysosma pleiantha Alnus japonica Ruellia tuberose Acacia xanthophloea Lannea stuhlmannii Maytenus obscura Plicosepalus sagittifolius Piper latifolium Morinda citrifolia Knema tenuinervia Deeringia amaranthoides Cynanchum hancoekianum Azadirachta indica Virola bicuhyba Sempervivum armenum Sempervivum arvense Hippophae salicifolia Hypoxis nyasica Astragalus membranaceus Maytenus macrocarpa Cephalotaxus Harrington Euphorbiacaeae Compositae Compositae Compositae Apocynaceae Convolvulaceae Rubiaceae Plantaginaceae Polydiaceae Labiatae Labiatae Ganodermataceae Euphorbiacaeae Compositae Euphorbiacaeae Oleaceae Phytolaccaceae Pinaceae Berberidaceae Betulaceae Acanthaceae Leguminosae Anacardiaceae Celastraceae Loranthaceae Piperaceae Rubiaceae Myristicaceae Amaranthaceae Asclepiadaceae Meliaceae Myristicaceae Crassulaceae Crassulaceae Elaeagnaceae Hypoxiaceae Leguminosae Celastraceae Cephlotaxaceae Latex Entire Entire Root Leaf Rhizome Bark Leaf Root Leaf Entire Fruitbody Root Root Entire Seed Root Strobilus Root Wood Bark Fruit Root Leaf Branches Leaf Root Stembark Fruit Entire Leaf Seed Leaf Leaf Fruit Rhizome Root Stembark Entire [99] [100] [101] [101] [102] [103] [104] [105] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [118] [118] [118] [119] [119] [120] [121] [122] [123] [124] [125] [125] [126] [127] [128] [129] [130] studies suggest that the consumption of food rich in fruits, vegetables and spices have a lower incidence of cancers (stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas and colon) [131-133]. Dietary source of anti cancer agents: Natural dietary agents including fruits, vegetables, and spices have drawn a great deal of attention from both the scientific community and the general public owing to their demonstrated ability to suppress cancers. Recent 13 Bhanot et al. International Journal of Phytomedicine 3 (2011) 09-26 Dietary agents consist of a wide variety of biologically active components that are responsible for the anti-cancer effects like curcumin, genistein, resveratrol, diallyl sulfide, S-allyl cysteine, allicin, lycopene, capsaicin, diosgenin, gingerol, ellagic acid, ursolic acid, silymarin, anethol, catechins, eugenol, isoeugenol, dithiolthiones, isothiocyanates, indole-3-carbinol, isoflavones, saponins, phytosterols, inositol hexaphosphate, Vitamin C, D-limonene, lutein, folic acid, beta carotene, selenium, Vitamin E and flavonoids (Table 3). Many of which have been used in traditional medicines for thousands of years. These dietary agents are believed to suppress the inflammatory processes that lead to transformation, hyperproliferation, and initiation of carcinogenesis. Their inhibitory influences may ultimately suppress the final steps of carcinogenesis i.e angiogenesis and metastasis [134]. Table 3: Dietary sources as anticancer agent. S. No. Botanical Name 1 Carica papaya, Family- Caricaceae 2 Glycyrrhiza glabra; Glycyrrhiza radix; Glycyrrhiza uralensis, Family- Leguminosae 3 Cannabis sativa, Family- Cannabiaceae 4 Rosmarinus officinalis, Family- Lamiaceae 5 Pueraria lobata radix, Family- Fabaceae 6 Glycine max, Family- Fabaceae 7 Prunus armeniaca, Family- Rosaceae 8 Zingiber officinale, Family- Zingiberaceae 9 Lycopersicon esculentum, Family- Solanaceae 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Source Compound Berries β-Cryptoxanthin Licorice root Glycyrrhizin Reference [135] [136] Hemp Rosemary [137] [138] [139] [139] [140] [141] [141] Cannabinol Carnosol Genistein Soybeans Genistein Apricots Carotenoids Tuber Gingerol Tomato Lycopene, Lutein, Kaempferol Piper nigrum; Piper longum, Family- Piperaceae Black pepper Purpurogallin; Piperine Ocimum sanctum, Family-Lamiaceae Basil Ursolic acid Betula alba, Family- Betulaceae Birch tree Betulinic acid Crocus sativus, Family- Iridaceae Saffron Carotenoids Silymarin marianum, Family- Asteraceae Milk thistle Silymarin Capsaicum annum; Capsaicum frutens, Family- Red chilli Capsaicinoids, Solanaceae Capsaicin Camellia sinensis, Family- Theaceae Green and Catechin and black teas theaflavins Vitis vinifera, Family- Vitaceae Grapes Resveratrol Daucus carota sativus, FamilyCarrot β-Carotene Apiaceae/umbelliferae Tabebuia avellanedae, Family- Bignoniaceae Lapacha tree Lapachone Citrus aurantium, Family- Rutaceae Orange Hesperidin Prunus dulcis, Family- Rosaceae Almond Morin Aloe arborescens, Family- Asphodelaceae Aloe vera Emodin Opium poppy, Family- Paparveraceae Poppy Morphine and its analogues Curcurbita moschata, Family-Cucurbitaceae Pumpkin β-Carotene Azadirachata indica, Family- Meliaceae Neem Polyphenolics 14 [142] [143] [144] [146] [147] [148] [149] [150] [151] [31] [152] [153,154] [155] [157] [158] [159] Marines as source of anti-cancer agents: Marine organisms are a rich source for natural products [160]. In recent time, advancement in deep-sea collection and aqua culture technology gives significant number of compounds derived from marine organisms entering preclinical and early clinical evaluation as potential anticancer agent [161,162]. Overall, more than 3000 new substances have been identified from marine organisms that demonstrate the great potential as a source of novel chemical classes [163]. Marine belongs to very diverse structural classes including polyketides, terpenes, steroids and peptides. The organisms yielding these bioactive marine compounds include invertebrate animals, algae, fungi and bacteria [164]. The first anticancer product didemnin B, a cyclic depsipeptide isolated from the tunicate Trididemnum solidum from marine source enter in clinical trials. Preliminary results showed a partial activity against non-Hodgkin’s lymphoma [165]. It can inhibit protein synthesis and arrest G1 phase of cell-cycle. Another depsipeptide Aplidine appear to be more active as comparison with didemninB in preclinical trial and does not produce life-threatening neuromuscular toxicity. Preclinical data indicate that aplidine is active against several tumors through blockade of cell-cycle progression at G1 phase [166]. There are number of ecteinascidins have been isolated from the marine source tunicate Ecteinascidia turbinata. One of these ecteinascidins (ET-743) was selected for clinical trials and antitumor effects have been observed in phase I studies [167]. ET743 is a tetrahydroisoquinilone alkaloid and they acts by selective alkylation of guanine residues in the DNA minor groove [168] and also interacts with nuclear proteins [169]. In Europe and the United States ET-743 is currently in phase II clinical trials [167]. The dolastatins are a class of peptides obtained from the Indian Ocean, Dolabella auricularia. These peptides have cytotoxic activity and now a day, dolastatin10 and dolastatin15 of this class have received the greatest clinical interest. Dolastatin10 has entered in Phase I and Phase II clinical trials, after showing significant antitumor activity in preclinical models [170]. Its mechanism of action involves inhibition of microtubule assembly ultimately result in cellcycle arrest in metaphase [171,172]. The bryostatins, 20 macrocyclic lactones isolated from Bugula neritina and other marine bryozoa. These macrocyclic compounds have shown significant activity against lymphocytic leukemia cell line [173]. Bryostatin1 has recently entered phase II clinical trials for the treatment of melanoma, non-Hodgkin’s lymphoma, renal cancer and colorectal cancer [174-176] and continues to be evaluated in phase I clinical trials. Bryostatin1 has been found to promote the normal growth of bone marrow progenitor cells, to provide in vivo protection against normally lethal doses of ionizing radiation and to serve as an immune stimulant, enhancing the normal production of interleukin2 and interferons [177]. Beside this there are the number of compounds isolated from marine as potential anti-cancer agents included in Table 4 [178,179]. Microorganisms as source of anticancer agents: Antitumor antibiotics are among the most important cancer chemotherapeutic agents, and include members of the anthracycline, bleomycin, actinomycin, mitomycin and aureolic acid families [6]. Clinically useful agents from these above families are the daunomycin and related agents like doxorubicin, idarubicin and epirubicin; the peptolides (exemplified by dactinomycin), the mitosanes (such as mitomycin C) and the glycosylated anthracenone mithramycin. The anthracyclines are among the most used antitumor antibiotics in the clinic and exert antitumor activity mainly by inhibiting topoisomerase II [180,181]. Table 4: Marine derived potential anticancer agent. S.No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Compound Aaptamine Organism Sponge Chemistry Alkaloid Mechanism of action Induction of p21 and G2/M cell cycle arrest Cortistatin A Sponge Alkaloid Selective inhibiton of angiogensis Aplidine Ascidian Depsipeptide Oxidation and inactivation of low molecular weight-protein tyrosine phosphatase activity Bastadine 6 Sponge Alkaloid Inhibition of angiogenesis in vitro and in vivo involves apoptosis Fucoxanthinol Ascidian Carotenoid Induction of apoptosis Lamellarin D Mollusk Alkaloid ErbB3 protein and PI3K- Akt pathway involved in necrosis induction Clavulone II Soft coral Prostanoid G1 cell cycle arrest and apoptosis Geodiamolides Sponge Peptide Disorganization of actin filaments Ircinin-1 Sponge Sesterterpene G1 phase inhibition and apoptosis induction Laxaphycins A and Bacterium Cyclic peptides Increased polyploidy by putative B topoisomerase II alterations Leptosins C and F Fungus Alkaloid DNA topoisomerase I and II inhibition and apoptosis induction Onnamide A Sponge Polyketide Protein synthesis inhibition Philinopside A Sea cucumber Saponin Inhibition of angiogenesis and receptor tyrosine kinases Variolin B Sponge Alkaloid Inhibition of cyclin-dependent kinases and apoptosis induction Aplidine Ascidian Depsipeptide Induction of apoptosis with concomitant G1 arrest and G2 blockage Ascididemin Ascidian Alkaloid Direct iminoquinone reduction and reactive oxygen species generation Cammbrescidin Sponge Alkaloid Induction of eythroid differentiation 800 and cell cycle arrest Dideoxypetrosynol Sponge Fatty acid Induction of apoptosis via A mitochondrial signaling pathway Dolastatin 10 Mollusc Peptide Binds to amino-terminal peptide of βtubulin containing cysteine Girolline Sponge Alkaloid Induction of G2/M cell cycle arrest and p53 proteasome recruitment Halichondrin B Sponge Macrolide Induction of mitotic blockage and analogues derivative apoptosis Lissoclinolide Ascidian Fatty acid G2/M cell cycle arrest Neoamphimedine Sponge Alkaloid Induction of topoisomerase II αmediated catenation of DNA Bhanot et al. International Journal of Phytomedicine 3 (2011) 09-26 24. Psammaplin A Sponge Alkaloid Inhibition of aminopeptidase N and suppression of angiogenesis in vitro 25. Alkylpyridinium Sponge Alkaloid Induction of apoptosis and reduced cell adhesion 26. Aeroplysinin Sponge Alkaloid 27. Bryostatin-1 Bryozoan Macrolide Induction of apoptosis on proliferating endothelial cells Potentiation of ara-C induced apoptosis by PKC-dependent release of TNF-α 28. Cephaiostatin Worm Steroid 29. Chondropsin A Sponge Macrolide 30. Dehydrothrysiferol Alga Triterpene 31. Diazonamide-A Ascidian Peptide Disruption of mitosis and cellular microtubules with inhibition of GTP hydrolysis 32. 33. Dictyostatin Dolastatin 11 Sponge Mollusc Polyketide Peptide 34. Ecteinascidin- 743 Ascidian 35. GA3 polysaccharide Hemiasterlin analogue Kahalalide F Alga Isoquinoline alkaloid Polysaccharide Induction of tubulin polymerization F-actin stabilization by connection between two long-pitch strands Telomere dysfunction increases susceptibility to ET-743 Inhibition of topoisomerase I and II Sponge Tripeptide Mollusc Depsipeptide Mollusc Fish Alkaloid Fatty acid 36. 37. 38. 39. Lamellarin D omega-3 fatty acids Many pharmaceutical agents have been discovered by screening natural products from a wide range of microorganisms. Rapamycin and its analogs are products of Streptomyces hygroscopicus have potent immunosuppressive activity. They inhibit signaling pathways required for T-cell activation and proliferation. Apoptosis and increased mitochondrial matrix density In Vitro inhibition of V-ATPase enzyme Enhanced apoptosis induction in estrogen receptor negative breast cancer cells Induction of microtubule depolymerisation Potent cytotoxicity and induction of necrosis Potent inhibition of topoisomerase I -- Rapamycin blocks progression of the cell cycle at middle-to-late G1 phase in T cells and B cells, and osteosarcoma and rhabdomyosarcoma cell lines, among others [182]. Geldanamycin is a benzoquinone ansamycin natural fermentation product and inhibits heat-shock protein HSP 90 [183]. 17 Table 5: Microorganism derived anti-cancer agents. S.No. 1. 2. Compound Actinomycin Bleomycin Microorganism Streptomyces spp. Streptomyces verticillus 3. 4. Daunomycin Doxorubicin Streptomyces coeruleorubidus Streptomyces Pneuceticus 5. 6. 7. Epirubicin Idarubicin Mitomycin C Streptomyces pneuceticus Streptomyces Pneuceticus Streptomyces caespitosus 8. 9. 10. Geldanamycin Rapamicin Wortamannin Streptomyces Hygroscopicus Streptomyces hygroscopicus Talaromyces wortmanni Wortmannin is a product of the fungus Talaromyces wortmanni and inhibits signal transduction pathways by forming a covalent complex with an active-site residue of phosphoinositide 3 kinase (PI3K), inhibiting PI3K activity [184] (Table 5). Thus, toxins that originally evolved to kill competing micoorganisms can have a variety of physiological effects in animals. In many cases, the targets of these compounds are components of signal transduction cascades that are conserved in many species, and that have been considered novel targets for anticancer drug discovery [185]. Conclusion: Natural products have been a prime source for the treatment of many forms of cancer, many of which are consumed daily with the diet. They provide significant protection against various cancers and many other diseases. 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