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Review on Molecular and Chemopreventive Potential of Nimbolide in Cancer

  • Elumalai, Perumal (Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras) ;
  • Arunakaran, Jagadeesan (Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras)
  • Received : 2014.09.07
  • Accepted : 2014.11.09
  • Published : 2014.12.31
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Abstract

Cancer is the most dreaded disease in human and also major health problem worldwide. Despite its high occurrence, the exact molecular mechanisms of the development and progression are not fully understood. The existing cancer therapy based on allopathic medicine is expensive, exhibits side effects; and may also alter the normal functioning of genes. Thus, a non-toxic and effective mode of treatment is needed to control cancer development and progression. Some medicinal plants offer a safe, effective and affordable remedy to control the cancer progression. Nimbolide, a limnoid derived from the neem (Azadirachta indica) leaves and flowers of neem, is widely used in traditional medical practices for treating various human diseases. Nimbolide exhibits several pharmacological effects among which its anticancer activity is the most promising. The previous studies carried out over the decades have shown that nimbolide inhibits cell proliferation and metastasis of cancer cells. This review highlights the current knowledge on the molecular targets that contribute to the observed anticancer activity of nimbolide related to induction of apoptosis and cell cycle arrest; and inhibition of signaling pathways related to cancer progression.

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References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-674. https://doi.org/10.1016/j.cell.2011.02.013
  2. Alyasiri NS, Mehdi SJ, Alam MS, Ali A, Mandal AK, Gupta S, et al. PTEN-mediated AKT activation contributes to the reduced apoptosis among Indian oral squamous cell carcinoma patients. J Cancer Res Clin Oncol 2012;138:103-109. https://doi.org/10.1007/s00432-011-1077-y
  3. Singh SR. Cancer stem cells: recent developments and future prospects. Cancer Lett 2013;338:1-2. https://doi.org/10.1016/j.canlet.2013.03.036
  4. Kaefer CM, Milner JA. The role of herbs and spices in cancer prevention. J Nutr Biochem 2008;19:347-361. https://doi.org/10.1016/j.jnutbio.2007.11.003
  5. Biswas K, Chattopadhyay I, Banerjee RK, Bandyopadhyay U. Biological activities and medicinal properties of neem (Azadirachta indica). Curr Sci 2002;82:1336-1345.
  6. Paul R, Prasad M, Sah NK. Anticancer biology of Azadirachta indica L (neem): a mini review. Cancer Biol Ther 2011;12:467-476. https://doi.org/10.4161/cbt.12.6.16850
  7. Subapriya R, Nagini S. Medicinal properties of neem leaves: a review. Curr Med Chem Anticancer Agents 2005;5:149-146. https://doi.org/10.2174/1568011053174828
  8. Subapriya R, Nagini S. Ethanolic neem leaf extract protects against N-methyl -N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in Wistar rats. Asian Pac J Cancer Prev 2003;4:215-223.
  9. Kumar S, Suresh PK, Vijayababu MR, Arunkumar A, Arunakaran J. Anticancer effects of ethanolic neem leaf extract on prostate cancer cell line (PC-3). J Ethnopharmacol 2006;105:246-250. https://doi.org/10.1016/j.jep.2005.11.006
  10. Gunadharini DN, Elumalai P, Arunkumar R, Senthilkumar K, Arunakaran J. Induction of apoptosis and inhibition of PI3K/Akt pathway in PC-3 and LNCaP prostate cancer cells by ethanolic neem leaf extract. J Ethnopharmacol 2011;134:644-650. https://doi.org/10.1016/j.jep.2011.01.015
  11. Anitha G, Raj JJ, Krishnan VR, Narasimhan S, Solomon KA, Rajan SS. Semi-synthetic modification of nimbolide to 6-homodesacetylnimbin and 6-desacetylnimbin and their cytotoxic studies. J Asian Nat Prod Res 2007;9:73-78. https://doi.org/10.1080/10286020500383742
  12. Rochanakij S, Thebtaranonth Y, Yenjai C, Yuthavong Y. Nimbolide, a constituent of Azadirachta indica, inhibits Plasmodium falciparum in culture. Southeast Asian J Trop Med Public Health 1985;16:66-72.
  13. Rojanapo W, Suwanno S, Somjaree R, Glinsukon T, Thebtaranont Y. Mutagenic and antibacterial activity testing of nimbolide and nimbic acid. J Sci Soc Thailand 1985;11:177-181. https://doi.org/10.2306/scienceasia1513-1874.1985.11.177
  14. Suresh G, Gopalakrishnan G, Wesley SD, Pradeep Singh ND, Malathi R, Rajan SS. Insect antifeedant activity of tetranortriterpenoids from the Rutales: a perusal of structural relations. J Agric Food Chem 2002;50:4484-4490. https://doi.org/10.1021/jf025534t
  15. Cohen E, Quistad GB, Casida JE. Cytotoxicity of nimbolide, epoxyazadiradione and other limonoids from neem insecticide. Life Sci 1996;58:1075-1081. https://doi.org/10.1016/0024-3205(96)00061-6
  16. Gupta SC, Prasad S, Reuter S, Kannappan R, Yadav VR, Ravindran J, et al. Modification of cysteine 179 of Ikappa-Balpha kinase by nimbolide leads to down-regulation of NF-kappaB-regulated cell survival and proliferative proteins and sensitization of tumor cells to chemotherapeutic agents. J Biol Chem 2010;285:35406-35417. https://doi.org/10.1074/jbc.M110.161984
  17. Kavitha K, Vidya Priyadarsini R, Anitha P, Ramalingam K, Sakthivel R, Purushothaman G, et al. Nimbolide, a neem limonoid abrogates canonical NF-kappaB and Wnt signaling to induce caspase-dependent apoptosis in human hepatocarcinoma (HepG2) cells. Eur J Pharmacol 2012;681:6-14. https://doi.org/10.1016/j.ejphar.2012.01.024
  18. Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Isobe S, et al. Antiproliferative effect on human cancer cell lines after treatment with nimbolide extracted from an edible part of the neem tree (Azadirachta indica). Phytother Res 2007;21:245-250. https://doi.org/10.1002/ptr.2058
  19. Elumalai P, Arunkumar R, Benson CS, Sharmila G, Arunakaran J. Nimbolide inhibits IGF-I-mediated PI3K/Akt and MAPK signalling in human breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem Funct 2014;32:476-484.
  20. Kigodi PG, Blasko G, Thebtaranonth Y, Pezzuto JM, Cordell GA. Spectroscopic and biological investigation of nimbolide and 28-deoxonimbolide from Azadirachta indica. J Nat Prod 1989;52:1246-1251. https://doi.org/10.1021/np50066a008
  21. Sastry BS, Suresh Babu K, Hari Babu T, Chandrasekhar S, Srinivas PV, Saxena AK, et al. Synthesis and biological activity of amide derivatives of nimbolide. Bioorg Med Chem Lett 2006;16:4391-4394. https://doi.org/10.1016/j.bmcl.2006.05.105
  22. Bodduluru LN, Kasala ER, Thota N, Barua CC, Sistla R. Chemopreventive and therapeutic effects of nimbolide in cancer: the underlying mechanisms. Toxicol In Vitro 2014;28:1026-1035. https://doi.org/10.1016/j.tiv.2014.04.011
  23. Sritanaudomchai H, Kusamran T, Kuakulkiat W, Bunyapraphatsara N, Hiransalee A, Tepsuwan A, et al. Quinone reductase inducers in Azadirachta indica A. Juss flowers, and their mechanisms of action. Asian Pac J Cancer Prev 2005;6:263-269.
  24. Priyadarsini RV, Manikandan P, Kumar GH, Nagini S. The neem limonoids azadirachtin and nimbolide inhibit hamster cheek pouch carcinogenesis by modulating xenobiotic-metabolizing enzymes, DNA damage, antioxidants, invasion and angiogenesis. Free Radic Res 2009;43:492-504. https://doi.org/10.1080/10715760902870637
  25. Harish Kumar G, Vidya Priyadarsini R, Vinothini G, Vidjaya Letchoumy P, Nagini S. The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis. Invest New Drugs 2010;28:392-401. https://doi.org/10.1007/s10637-009-9263-3
  26. Gupta SC, Prasad S, Sethumadhavan DR, Nair MS, Mo YY, Aggarwal BB. Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment. Clin Cancer Res 2013;19:4465-4476. https://doi.org/10.1158/1078-0432.CCR-13-0080
  27. Rahmani A, Alzohairy M, Mandal AK, Rizvi MA. Expressional evaluation of androgen receptor in transitional cell carcinoma of urinary bladder patients. Br J Med Med Res 2011;1:233-238. https://doi.org/10.9734/BJMMR/2011/304
  28. Babiker AY, Rahmani AH, Abdalaziz MS, Albutti A, Aly SM, Ahmed HG. Expressional analysis of p16 and cytokeratin19 protein in the genesis of oral squamous cell carcinoma patients. Int J Clin Exp Med 2014;7:1524-1530.
  29. Babykutty S, S PP, J NR, Kumar MA, Nair MS, Srinivas P, et al. Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-kappaB in colon cancer cells. Mol Carcinog 2012;51:475-490. https://doi.org/10.1002/mc.20812
  30. Elumalai P, Gunadharini DN, Senthilkumar K, Banudevi S, Arunkumar R, Benson CS, et al. Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway. Toxicol Lett 2012;215:131-142. https://doi.org/10.1016/j.toxlet.2012.10.008
  31. Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J, et al. Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res 2004;64:286-291. https://doi.org/10.1158/0008-5472.CAN-03-1242
  32. Sachdev D, Hartell JS, Lee AV, Zhang X, Yee D. A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. J Biol Chem 2004;279:5017-5024. https://doi.org/10.1074/jbc.M305403200
  33. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004;4:505-518. https://doi.org/10.1038/nrc1387
  34. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261-1274. https://doi.org/10.1016/j.cell.2007.06.009
  35. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002;14:381-395. https://doi.org/10.1016/S0898-6568(01)00271-6
  36. Tokunaga E, Kimura Y, Oki E, Ueda N, Futatsugi M, Mashino K, et al. Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone- treated patients. Int J Cancer 2006;118:284-289. https://doi.org/10.1002/ijc.21358
  37. Bartlett JM, A'Hern R, Piper T, Ellis IO, Dowsett M, Mallon EA, et al. Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer. Breast Cancer Res Treat 2013;138:773-781. https://doi.org/10.1007/s10549-013-2489-y
  38. Perez-Tenorio G, Stal O; Southeast Sweden Breast Cancer Group. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer 2002;86:540-545. https://doi.org/10.1038/sj.bjc.6600126
  39. Vazquez F, Sellers WR. The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim Biophys Acta 2000;1470:M21-M35.
  40. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943-1947. https://doi.org/10.1126/science.275.5308.1943
  41. Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, et al. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer 2004;112:407-410. https://doi.org/10.1002/ijc.20447
  42. Karkare S, Chhipa RR, Anderson J, Liu X, Henry H, Gasilina A, et al. Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell-cycle arrest and suppresses glioblastoma growth. Clin Cancer Res 2014;20:199-212. https://doi.org/10.1158/1078-0432.CCR-13-0762
  43. Raja Singh P, Arunkumar R, Sivakamasundari V, Sharmila G, Elumalai P, Suganthapriya E, et al. Anti-proliferative and apoptosis inducing effect of nimbolide by altering molecules involved in apoptosis and IGF signalling via PI3K/Akt in prostate cancer (PC-3) cell line. Cell Biochem Funct 2014;32:217-228. https://doi.org/10.1002/cbf.2993
  44. Moynagh PN. The NF-kappaB pathway. J Cell Sci 2005;118(Pt 20):4589-4592. https://doi.org/10.1242/jcs.02579
  45. Kearns JD, Basak S, Werner SL, Huang CS, Hoffmann A. IkappaBepsilon provides negative feedback to control NFkappaB oscillations, signaling dynamics, and inflammatory gene expression. J Cell Biol 2006;173:659-664. https://doi.org/10.1083/jcb.200510155
  46. Elumalai P, Brindha Mercy A, Arunkamar R, Sharmila G, Bhat FA, Balakrishnan S, et al. Nimbolide inhibits invasion and migration, and down-regulates uPAR chemokine gene expression, in two breast cancer cell lines. Cell Prolif 2014;47:540-552. https://doi.org/10.1111/cpr.12148
  47. Sachdev D. Regulation of breast cancer metastasis by IGF signaling. J Mammary Gland Biol Neoplasia 2008;13:431-441. https://doi.org/10.1007/s10911-008-9105-5
  48. Bourboulia D, Stetler-Stevenson WG. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 2010;20:161-168. https://doi.org/10.1016/j.semcancer.2010.05.002
  49. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer 2004;4:540-550. https://doi.org/10.1038/nrc1388
  50. Tang L, Han X. The urokinase plasminogen activator system in breast cancer invasion and metastasis. Biomed Pharmacother 2013;67:179-182. https://doi.org/10.1016/j.biopha.2012.10.003
  51. Kong D, Li Y, Wang Z, Banerjee S, Sarkar FH. Inhibition of angiogenesis and invasion by 3,3'-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Res 2007;67:3310-3319. https://doi.org/10.1158/0008-5472.CAN-06-4277
  52. Sherr CJ. Cancer cell cycles. Science 1996;274:1672-1677. https://doi.org/10.1126/science.274.5293.1672
  53. Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Tsushida T. Inhibition of colon cancer (HT-29) cell proliferation by a triterpenoid isolated from Azadirachta indica is accompanied by cell cycle arrest and up-regulation of p21. Planta Med 2006;72:917-923. https://doi.org/10.1055/s-2006-946694
  54. Harish Kumar G, Chandra Mohan KV, Jagannadha Rao A, Nagini S. Nimbolide a limonoid from Azadirachta indica inhibits proliferation and induces apoptosis of human choriocarcinoma (BeWo) cells. Invest New Drugs 2009;27:246-252. https://doi.org/10.1007/s10637-008-9170-z
  55. Priyadarsini RV, Murugan RS, Sripriya P, Karunagaran D, Nagini S. The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells. Free Radic Res 2010;44:624-634. https://doi.org/10.3109/10715761003692503
  56. Takahashi-Yanaga F, Sasaguri T. GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy. Cell Signal 2008;20:581-589. https://doi.org/10.1016/j.cellsig.2007.10.018
  57. Yuan J, Yan R, Kramer A, Eckerdt F, Roller M, Kaufmann M, et al. Cyclin B1 depletion inhibits proliferation and induces apoptosis in human tumor cells. Oncogene 2004;23:5843-5852. https://doi.org/10.1038/sj.onc.1207757
  58. LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev 1997;11:847-862. https://doi.org/10.1101/gad.11.7.847
  59. Moldovan GL, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell 2007;129:665-679. https://doi.org/10.1016/j.cell.2007.05.003
  60. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116:205-219. https://doi.org/10.1016/S0092-8674(04)00046-7
  61. Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, Griffith C, et al. Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer. Clin Cancer Res 2006;12(3 Pt 2):1024s-1030s. https://doi.org/10.1158/1078-0432.CCR-05-2127
  62. Fesik SW. Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 2005;5:876-885. https://doi.org/10.1038/nrc1736
  63. Ashkenazi A, Herbst RS. To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest 2008;118:1979-1990. https://doi.org/10.1172/JCI34359
  64. Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol 2007;8:405-413.
  65. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002;108:153-164. https://doi.org/10.1016/S0092-8674(02)00625-6
  66. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999;6:99-104. https://doi.org/10.1038/sj.cdd.4400476
  67. Zhou Y, Peng Y, Mao QQ, Li X, Chen MW, Su J, et al. Casticin induces caspase-mediated apoptosis via activation of mitochondrial pathway and upregulation of DR5 in human lung cancer cells. Asian Pac J Trop Med 2013;6:372-378. https://doi.org/10.1016/S1995-7645(13)60041-3
  68. Gupta SC, Reuter S, Phromnoi K, Park B, Hema PS, Nair M, et al. Nimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent up-regulation of death receptors, p53, and Bax. J Biol Chem 2011;286: 1134-1146. https://doi.org/10.1074/jbc.M110.191379

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