A critical review of anticancer properties of Withania somnifera (L.) Dunal with respect to the biochemical mechanisms of its phytochemical constituents
DOI:
https://doi.org/10.14719/pst.2021.8.2.969Keywords:
anti-cancer activity, phytochemistry, Withania somnifera, WithaferinAbstract
Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
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Maurya R, Akanksha, Jayendra. Chemistry and pharmacology of Withania coagulans: An ayurvedic remedy. J Pharm Pharmacol. 2010;62:153–60. https://doi.org/10.1211/jpp.62.02.0001
Jonh J. Therapeutic potential of Withania somnifera: A report on phyto pharmacological properties. Int J Pharm Sci Res. 2014;5(21):31–48. https://doi.org/10.13040/IJPSR.0975-8232.5(6).2131-48
Mahendra R, Priti S J, Gauravi A, Carolina AdS. Anticancer activities of Withania somnifera: Current research, formulations, and future perspectives. Pharm Biol. 2016;54(2):189-97. https://doi.org/10.3109/13880209.2015.1027778
Soladoye MO, Amusa NA, Raji-Esan SO, Chukwuma EC, Taiwo AA. Ethnobotanical survey of anti-cancer plants in Ogun State, Nigeria. Ann Biol Res. 2010;1(4):261-73.
Manju N, Shahnwaj T, Ashwani Kumar G. Enhancement in growth and yield of ashwagandha (Withania somnifera (L.) Dunal) by counteracting effect of infrared supplemented with ultraviolet-B radiation. Int J Sci Res. 2016;5(2):2209-14.
Bhattacharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: An experimental study using a rat model of chronic stress. Pharmacol Biochem Behav. 2003;75(5):47–55. https://doi.org/10.1016/s0091-3057(03)00110-2
Widodo N, Kaur K, Shrestha B, Takagi Y, Ishii T, Wadhwa R, et al. Selective killing of cancer cells by leaf extract of Ashwagandha: identification of a tumor-inhibitory factor and the first molecular insights to its effect. Clin Cancer Res. 2007;13: 2298-06. https://doi.org/10.1158/1078-0432.CCR-06-0948
Babli H, Shruti S, Suman ST. Withania somnifera root extract has potent cytotoxic effect against human malignant melanoma cells. PLoS ONE. 2015;10(9):e0137498. https://doi.org/10.1371/journal.pone.0137498
Wadhwa R, Singh R, Gao R, Shah N, Widodo N, Nakamoto T, et al. Water extract of ashwagandha leaves has anticancer activity: Identification of an active component and its mechanism of action. PLoS ONE. 2013;8(10):e77189. https://doi.org/10.1371/journal.pone.0077189
Mishra L, Singh B, Dagenais S. Scientific basis for the therapeutic use of Withania somnifera. (Ashwagandha): A review. Altern Med Rev. 2000;5(3):34-46. PMID: 10956379.
Matsuda H, Murakami T, Kishi A, Yoshikawa M. Structures of withanosides I. II, III: IV, V, VI, and VII, new withanolide glycosides, from the roots of Indian Withania somnifera Dunal and inhibitory activity for tachyphylaxis to clonidine in isolated guinea-pig ileum. Bioorg Med Chem. 2001;9(1):1499-507. https://doi.org/10.1016/s0968-0896(01)00024-4
Bolleddula J, Fitch W, Vareed S, Nair M. Identification of metabolites in Withania sominfera fruits by liquid chromatography and high-resolution mass spectrometry. Rapid Commun Mass Spectrom. 2012;26:1277-90. https://doi.org/10.1002/rcm.6221.
Xu Y, Gao S, Bunting DP, Gunatilaka AAL. Unusual withanolides from aeroponically grown Withania somnifera. Phytochemistry. 2011;72:518-22. https://doi.org/10.1016/j.phytochem.2010.12.020
Chen LX, He H, Qiu F. Natural withanolides: An overview. Nat Prod Rep. 2011;28:705–40. https://doi.org/10.1039/c0np00045k
Ray AB, Gupta M. Withasteroids, a group of naturally occurring steroidal lactones. Prog Chem Org Nat Prod. 1994;63:1–106. https://doi.org/10.1007/978-3-7091-9281-8_1
Kulkarni S, Singh K, Bishnoi M. Comparative behavioural profile of newer antianxiety drugs on different mazes. Indian J Exp Biol. 2008;46:633-38.
Mohammad HM, Elisabeth M, Mercedes B, Rosa MC, Javier P. Steroidal lactones from Withania somnifera, an ancient plant. Molecules. 2009;14:2373-93. https://doi.org/10.3390/molecules14072373
Uvais MSS, Sotheeswaran S, Balasubrmaniam S, El-Kawi MABD, Slatkin DJ, Schiff Jr PL. Pachyovatamine, a bisbenzylisoquinoline alkaloid and other alkaloids from Pachygone ovata. Phytochemistry. 1985;24:589-92.
Fazal Hussain S, Khan L, Guinaudeau H, Leet JE, Freyer AJ, Shamma M. The alkaloidal profile of Cocculus pendulus. Tetrahedron. 1984;40(13):2513–17. https://doi.org/10.1016/s0040-4020(01)83503-1
Leet JE, Hussain SF, Minard RD, Shamma M. Sindamine, punjabine and gilgitine: three new secobisbenzylisoquinoline alkaloids. Heterocycles. 1982;19:2355–60.
Khan PM, Ahmad S, Rubnawaz H, Malik A. The first of withanolide from the family Labiatae. Phytochemistry. 1999;51:669–71. https://doi.org/10.1016/S0031-9422(99)00045-X
Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med. 2015;5. https://doi.org/10.1101/cshperspect.a006098
Aggarwal B, Ichikawa H, Garodia P, Weerasinghe P, Sethi G, Bhatt I, et al. From traditional ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer. Expert Opin Ther Targets. 2006;10(1):87-118. https://doi.org/10.1517/14728222.10.1.87
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013
Charames GS, Bapat B. Genomic instability and cancer. Curr Mol Med. 2003;3(7):589–96. https://doi.org/10.2174/1566524033479456
Szarc vel Szic K, Beeck KOd, Ratman D, Wouters A, Beck I, Declerck K, et al. Pharmacological levels of Withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells. PLoS One. 2014; 9(2):e87850. https://doi.org/10.1371/journal.pone.0087850
Nashi W, Yasuomi T, G. SB, Tetsuro I, C. KS, Renu W. Selective killing of cancer cells by leaf extract of Ashwagandha: Components, activity and pathway analyses. Cancer Letters. 2008;262:37–47. https://doi.org/10.1371/journal.pone.0013536
Alok SC, Shanker, Lalit KT, Mahendra S, Rao ChV. Herbal medicine for market potential in India. Academic Journal of Plant Sciences. 2008;1(2):26-36.
Shoeb M. Anticancer agents from medicinal plants. Bangladesh J Pharmacol. 2006;1:35–41. https://doi.org/10.3329/bjp.v1i2.486
Schmidt M, Bastians H. Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug Resist Updat. 2007;10:162–81. https://doi.org/10.1016/j.drup.2007.06.003
Dholwani KK, Saluja AK, Gupta AR, Shah DR. A review on plant – derived natural products and their analogs with anti-tumor activity. Indian J Pharmacol. 2008;40(2):49–58. https://doi.org/ 10.4103/0253-7613.41038
Srivastava V, Negi AS, Kumar JK, Gupta MM, Suman PS. Plant-based anticancer molecules: a chemical and biological profile of some important leads. Bioorg Med Chem. 2005;13:5892–908. https://doi.org/10.1016/j.bmc.2005.05.066
Grin B, Mahammad S, Wedig T, Cleland M, Tsai L, Herrmann H et al. Withaferin A alters intermediate filament organization, cell shape and behavior. PLoS ONE 7(6): e39065. 2012. https://doi.org/ 10.1371/journal.pone.0039065
Shah N, Kataria H, Kaul S, Ishii T, Kaur G, Wadhwa R. Effect of the alcoholic extract of Ashwagandha leaves and its components on proliferation, migration and differentiation of glioblastoma cells: combinational approach for enhanced differentiation. Cancer Sci. 2009;100(9):1740-47. https://doi.org/10.1111/j.1349-7006.2009.01236.x
Jayaprakasam B, Padmanabhan K, Nair M. Withanamides in Withania somnifera fruit protect PC-12 cells from beta-amyloid responsible for Alzheimer’s disease. Phytother Res. 2009;24:859–63. https://doi.org/10.1002/ptr.3033
Kuboyama T, Tohda C, Komatsu K. Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol. 2005;144:961–71. https://doi.org/10.1038/sj.bjp.0706122
Kumar P, Kumar A. Possible neuroprotective effect of Withania somnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of Huntington’s disease. J Med Food. 2009;12(3):591–600. https://doi.org/10.1089/jmf.2008.0028
Llanos GG, Araujo LM, Jimenez IA, Moujir LM, Bazzocchi IL. Withaferin A-related steroids from Withania aristata exhibit potent antiproliferative activity by inducing apoptosis in human tumor cells. Eur J Med Chem. 2012;54:499–511. https://doi.org/ 10.1016/j.ejmech.2012.05.032
Malik F, Singh J, Khajuria A, Suri KA, Satti NK, Singh S, et al. A standardized root extract of Withania somnifera and its major constituent withanolide-A elicit humoral and cell-mediated immune responses by up regulation of Th1-dominant polarization in BALB/c mice. Life Sci. 2007;80:1525–38. https://doi.org/10.1016/j.lfs.2007.01.029
Mirjalili MH, Moyano E, Bonfill M, Cusido R, Palazón J. Steroidal lactones from Withania somnifera, an ancient plant for novel medicine. Molecules. 2009;14:2373–93. https://doi.org/10.3390/molecules14072373
Ven Murthy MR, Ranjekar PK, Ramassamy C, Deshpande M. Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: Ashwagandha. Cent Nerv Syst Agents Med Chem. 2010;10(3):238–46. https://doi.org/10.2174/1871524911006030238
Ichikawa H, Takada Y, Shishodia S, Jayaprakasam B, Nair MG, Aggarwal BB. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-jB) activation and NF-jB-regulated gene expression. Mol Cancer Ther. 2006;5(6):1434–45. https://doi.org/ 10.1158/1535-7163.MCT-06-0096
Mahrous RSR, Ghareeb DA, Fathy HM, Abu EL-Khair RM, Omar AA. The protective effect of Egyptian Withania somnifera against Alzeheimer’s. Med Aromat Plants. 2017;6:285. https://doi.org/ 10.4172/2167-0412.1000285
Scartezzini P, Antognoni F, Conte L, Maxia A, Troìa A, Poli F. Genetic and phytochemical difference between some Indian and Italian plants of Withania somnifera (L.) Dunal. Nat Prod Res. 2007;21(10):923–32. https://doi.org/10.1080/14786410701500169
Jayaprakasam B, Zhang Y, Seeram NP, Nair MG. Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life Sci. 2003;74:125-32. https://doi.org/10.1016/j.lfs.2003.07.007
Mayola E, Gallerne C, Esposti DD, Martel C, Pervaiz S, Larue L, et al. Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2. Apoptosis. 2011;16:1014-27. https://doi.org/ 10.1007/s10495-011-0625-x
Widodo N, Priyandoko D, Shah N, Wadhwa R, Kaul SC. Selective killing of cancer cells by ashwagandha leaf extract and its component withanone involves ROS signaling.. PLoS ONE. 2010;5(10):e13536. https://doi.org/10.1371/journal.pone.0013536
Davis L, Kuttan G. Effect of Withania somnifera on DMBA induced carcinogenesis. J Ethnopharmacol. 2001;75:165–68. https://doi.org/10.1016/s0378-8741(00)00404-9
Srinivasan S, Ranga RS, Burikhanov R, Han S, Chendil D. Par-4-dependent apoptosis by the dietary compound Withaferin A in prostate cancer cells. Cancer Res. 2007;67(1):246–53. https://doi.org/10.1158/0008-5472.CAN-06-2430
Oh JH, Lee T, Kim SH, Choi YH, Lee SH, Lee JM, et al. Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation. Apoptosis. 2008;13:1494–04. https://doi.org/10.1007/s10495-008-0273-y
Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res. 2008;68(18):7661–69. https://doi.org/10.1158/0008-5472.CAN-08-1510
Mandal C, Dutta A, Mallick A, Chandra S, Misra L, Sangwan RS, et al. Withaferin A induces apoptosis by activating p38 mitogen- activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. Apoptosis. 2008;13:1450–64. https://doi.org/ 10.1007/s10495-008-0271-0
Kaileh M, Vanden Berghe W, Heyerick A, Horion J, Piette J, Libert C, et al. Withaferin A strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity. J Biol Chem. 2007;282:4253–64. https://doi.org/ 10.1074/jbc.M606728200
Koduru S, Kumar R, Srinivasan S, Evers MB, Damodaran C. Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis. Mol Cancer Ther. 2010;9(1):202–10. https://doi.org/10.1158/1535-7163.MCT-09-0771
Lee J, Sehrawat A, Singh SV. Withaferin A causes activation of Notch2 and Notch4 in human breast cancer cells. Breast Cancer Res Treat. 2012;136(1):45–56. https://doi.org/10.1007/s10549-012-2239-6
Mohan R, Hammers HJ, Bargagna-Mohan P, Zhan XH, Herbstritt CJ, Ruiz A, et al. Withaferin A is a potent inhibitor of angiogenesis. Angiogenesis. 2004;7:115–22. https://doi.org/10.1007/s10456-004-1026-3
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11:577-90. https://doi.org/10.1016/s1097-2765(03)00050-9
Dumont P, Leu JI, Della Pietra AC, George D, Murphy M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003;33:357-65. https://doi.org/10.1038/ng1093
Wadhwa R, Yaguchi T, Hasan MK, Mitsui Y, Reddel RR, Kaul SC. Hsp70 family member, mot-2/mthsp70/ GRP75, binds to the cytoplasmic sequestration domain of the p53 protein. Exp Cell Res. 2002;274(2):246-53. https://doi.org/10.1006/excr.2002.5468
Wadhwa R, Kaul SC, Mitsui Y, Sugimoto Y. Differential subcellular distribution of mortalin in mortal and immortal mouse and human fibroblasts. Exp Cell Res. 1993;207(44):2-8.
Chahar MK, Sharma N, Dobhal MP, Joshi YC. Flavonoids: a versatile source of anticancer drugs. Pharmacogn Rev. 2011;5(9):1–12. https://doi.org/10.4103/0973-7847.79093
Zhang X, Samadi AK, Roby KF, Timmermann B, Cohen MS. Inhibition of cell growth and induction of apoptosis in ovarian carcinoma cell lines CaOV3 and SKOV3 by natural withanolide Withaferin A. Gynecol Oncol. 2012;124:606-12. https://doi.org/10.1016/j.ygyno.2011.11.044
Zhang X, Mukerji R, Samadi AK, Cohen MS. Down-regulation of estrogen receptor-alpha and rearranged during transfection tyrosine kinase is associated with withaferin a-induced apoptosis in MCF-7 breast cancer cells.. BMC Complement Altern Med. 2011;11:84. https://doi.org/10.1186/1472-6882-11-84
Ram VR, Suman S, Trinath PD, Joe EL, Chendil D. Withaferin A, a steroidal lactone from Withania somnifera, induces mitotic catastrophe and growth arrest in prostate cancer cells. J Nat Prod. 2013;76:1909-15. https://doi.org/10.1021/np400441f
Muralikrishnan G, Dinda AK, Shakeel F. Immunomodulatory effects of Withania somnifera on azoxymethane induced experimental colon cancer in mice. Immunol Invest. 2010;39:688–98. https://doi.org/10.3109/08820139.2010.487083
Nagaraj S, Gabrilovich DI. Myeloid-derived suppressor cells in human cancer. Cancer J. 2010;16(4):348–53. https://doi.org/10.1097/PPO.0b013e3181eb3358
Kodumudi KN, Weber A, Sarnaik AA, Pilon-Thomas S. Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma. J Immunol. 2012;189:5147–54. https://doi.org/10.4049/jimmunol.1200274
Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother. 2010;59:1593–1600. https://doi.org/10.1007/s00262-010-0855-8
Sinha P, Clements VK, Ostrand-Rosenberg S. Interleukin- 13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis. Cancer Res. 2005;65(24):11743-51. https://doi.org/10.1158/0008-5472.CAN-05-0045
Sinha P, Clements VK, Ostrand-Rosenberg S. Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol. 2005;174:636–45. https://doi.org/10.4049/jimmunol.174.2.636
Christina AJM, Joseph DG, Packialakshmi M, Kothai R, Robert SJH, Chidambaranathan N, et al. Anticarcinogenic activity of Withania somnifera Dunal against Dalton’s ascitic lymphoma. J Ethnopharmacol. 2004;93:359–61. https://doi.org/10.1016/j.jep.2004.04.004
Padmavathi B, Rath PC, Rao AR, Singh RP. Roots of Withania somnifera inhibit forestomach and skin carcinogenesis in mice. Evid Based Complement Alternat Med. 2005;2(1):99–105. https://doi.org/10.1093/ecam/neh064
Senthilnathan P, Padmavathi R, Magesh V, Sakthisekaran D. Chemotherapeutic efficacy of paclitaxel in combination with Withania somnifera on benzo(a)pyrene induced experimental lung cancer. Cancer Sci. 2006;97(7):658–64. https://doi.org/10.1111/j.1349-7006.2006.00224.x
Leyon PV, Kuttan G. Effect of Withania somnifera on B16F-10 melanoma induced metastasis in mice. Phytother Res. 2004;18:118–22. https://doi.org/10.1002/ptr.1378.
Wafaa Abdallah A, Mohamed A, Nasser EA, Doaa E. Potential toxicity of Egyptian ashwagandha: Significance for their therapeutic bioactivity and anticancer properties. Intl J Sci Res. 2015;4(2):2170-76.
Scartezzini P, Speroni E. Review on some plants of Indian traditional medicine with antioxidant activity. J Ethnopharmacol. 2000;71:23-43. https://doi.org/10.1016/s0378-8741(00)00213-0
Senthilnathan P, Padmavathi R, Magesh V, Sakthisekaran D. Modulation of TCA cycle enzymes and electron transport chain systems in experimental lung cancer. Life Sci. 2006;78:1010-14. https://doi.org/10.1016/j.lfs.2005.06.005
Samuel T, Okada K, Hyer M, Welsh K, Zapata JM, Reed JC. cIAP1 localizes to the nuclear compartment and modulates the cell cycle. Cancer Res. 2005;65(1):210-18. PMID: 15665297.
Prakash J, Gupta SK, Dinda AK. Withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in Swiss albino mice. Nutr Cancer. 2002;42(1):91-97. https://doi.org/ 10.1207/S15327914NC421_12
Patti R, Gumired K, Reddanna P, Sutton LN, Philips PC, Reddy CD. Overexpression of cyclooxygenase-2 (COX-2) in human primitive neuroectodermal tumors: effect of celecoxib and rofecoxib. Cancer Lett. 2002;180:13–21. https://doi.org/10.1016/s0304-3835(02)00003-4
Ohno R, Yoshinaga K, Fujita T, Hasegawa K, Iseki H, Tsunozaki H, Ichikawa W, et al. Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma. Cancer. 2001;91(10):1876-81. PMID: 11346869.
Khuder SA, Mutgi AB. Breast cancer and NSAID use: a meta-analysis. Br J Cancer. 2001;84(9):1188–92. https://doi.org/10.1054/bjoc.2000.1709
Smith WL, De Witt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000;69:145–82. https://doi.org/10.1146/annurev.biochem.69.1.145
Jayaprakasam B, Nair MG. Cyclooxygenase-2 enzyme inhibitory withanolides from Withania somnifera leaves. Tetrahedron. 2003;59(6):841-49. https://doi.org/10.1016/S0040-4020(02)01601-0
Kaur K, Rani G, Widodo N, Nagpal A, Taira K, Kaul SC, et al. Evaluation of the anti-proliferative and anti-oxidative activities of leaf extract from in vivo and in vitro raised Ashwagandha. Food Chem Toxicol. 2004;42:2015–20. https://doi.org/ 10.1016/j.fct.2004.07.015
Rajeev N, Sarita K, Parul J, Alka P. Anticancer activity of Withania somnifera (leaves) flavonoids compound. Int J Pharm Sci Rev Res. 2013;19(1):103-06.
Mathur S, Kaur P, Sharma M, Katyal A, Singh B, Tiwari M, et al. The treatment of skin carcinoma, induced by UV B radiation, using 1-oxo-5beta, 6beta-epoxy-witha-2-enolide, isolated from the roots of Withania somnifera, in a rat model. Phytomedicine. 2004;11:452–60. https://doi.org/10.1016/j.phymed.2003.05.004
Singh D, Aggarwal A, Maurya R, Naik S. Withania somnifera inhibits NF-kappaB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells. Phytother Res. 2007;21:905–13. https://doi.org/10.1002/ptr.2180
Senthil V, Ramadevi S, Venkatakrishnan V, Giridharan P, Lakshmi BS, Vishwakarma RA, et al. Withanolide induces apoptosis in HL-60 leukemia cells via mitochondria mediated cytochrome c release and caspase activation. Chem Biol Interact. 2007;167:19–30. https://doi.org/10.1016/j.cbi.2007.01.004
Singh DD, Dey CS, Bhutani KK. Downregulation of p34cdc2 expression with aqueous fraction from Withania somnifera for a possible molecular mechanism of anti-tumor and other pharmacological effects. Phytomedicine. 2001;8(6):492–94.
Iuvone T, Esposito G, Capasso F, Izzo AA. Induction of nitric oxide synthase expression by Withania somnifera in macrophages. Life Sci. 2003;72:1617–25. https://doi.org/10.1016/s0024-3205(02)02472-4
Oza VP, Parmar PP, Kumar S, Subramanian RB. Anticancer properties of highly purified L-asparaginase from Withania somnifera L. against acute lymphoblastic leukemia. Appl Biochem Biotechnol. 2010;160:1833–40. https://doi.org/10.1007/s12010-009-8667-z.
Anjaneyulu ASR, Rao DS, Le Quesne PW. Studies in natural products chemistry: Structure and chemistry (Part F). Atta-ur-Rahman. 1998;20:135–261.
Dai ZJ, Wang XJ, Li ZF, Ji ZZ, Ren HT, Tang W, et al. Scutellaria barbata extract induces apoptosis of hepatoma H22 cells via the mitochondrial pathway involving caspase-3. World J Gastroenterol. 2008;14(48):7321–28. PMID: 19109865.
Shafik NF, Elshimy RAA, Rahouma M, Rabea AM. Circulating MiR-150 and miR-130b as promising novel biomarkers for hepatocellular carcinoma. Cancer Biol. 2017;7(2):1–8. https://doi.org/10.7537/marscbj070217.01
El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73. https://doi.org/ 10.1053/j.gastro.2011.12.061
Tejeda-Maldonado J, Garcia-Juarez I, Aguirre-Valadez J, González-Aguirre A, Vilatobá-Chapa M, Armengol-Alonso A, et al. Diagnosis and treatment of hepatocellular carcinoma: An update. World J Hepatol. 2015;7(3):362–76. https://doi.org/10.4254/wjh.v7.i3.362
Samlowski WE, Yim CY, McGregor JR, Kwon OD, Gonzales S, Hibbs Jr JB. Effectiveness and toxicity of protracted nitric oxide synthesis inhibition during IL-2 treatment of mice. J Immunother Emphasis Tumor Immunol. 1995;18(3):166–78. https://doi.org/10.1097/00002371-199510000-00004
Best J, Schotten C, Theysohn JM, Wetter A, Muller S, Radunz S, et al. Novel implications in the treatment of hepatocellular carcinoma. Ann Gastroenterol. 2017;30(1):23–32. PMID: 28042235.
Karaman B, Battal B, Sari S, Verim S. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J Gastroenterol. 2014;20(47):18059–60. PMID: 25548509.
Njamen D, Zingue S, Mvondo MA, Magne Nde CB. The efficacy of some comestible natural products in treatment of cancer. Altern Integr Med. 2014;3:158. https://doi.org/10.4172/2327-5162.1000158
Morishima N, Nakanishi K, Takenouchi H, Shibata T, Yasuhiko Y. An endoplasmic reticulum stress-specific caspase cascade in apoptosis. Cytochrome C-independent activation of caspase-9 by caspase- 12. J Biol Chem. 2002;277(37):34287–94. https://doi.org/ 10.1074/jbc.M204973200
Pretorius E, Oberholzer HM, Becker PJ. Comparing the cytotoxic potential of Withania somnifera water and methanol extracts. Afr J Tradit Complement Altern Med. 2009;6(3):275–80. https://doi.org/10.4314/ajtcam.v6i3.57173
Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271-77. https://doi.org/10.1200/JCO.2009.25.9820
Winters M. Ancient medicine, modern use: Withania somnifera and its potential role in integrative oncology. Altern Med Rev. 2006;11(4):269-77. PMID: 17176166.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007;70(3):461-77. https://doi.org/ 10.1021/np068054v
DeSantis C, Naishadham D, Jemal A. Cancer statistics for African Americans, 2013. CA: A Cancer J Clin. 2013;63:151-66. https://doi.org/10.3322/caac.21173
Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nature Clinical Practice Urology. 2009;6(2):76-85. https://doi.org/10.1038/ncpuro1296
Nacusi LP, Tindall DJ. Targeting 5?-reductase for prostate cancer prevention and treatment. Nat Rev Urology. 2011;8:378-84. https://doi.org/10.1038/nrurol.2011.67
Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers – a different disease. Nat Rev Cancer. 2007;7:778–89. https://doi.org/ 10.1038/nrc2190
Bonomi PD, Finkelstein DM, Ruckdeschel JC, Blum RH, Green MD, Mason B, et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV nonsmall- cell lung cancer: a study of the Eastern cooperative oncology group. J Clin Oncol. 1989;7(11):1602–13. https://doi.org/ 10.1200/JCO.1989.7.11.1602
Fukuoka M, Furuse K, Saijo N, Nishiwaki Y, Ikegami H, Tamura T, et al. Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus Cisplatin and Etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst. 1991;83(12):855–61. https://doi.org/10.1093/jnci/83.12.855
Said HM. Hamdard Pharmacopeia of Eastern Medicine. The Times Press, Karachi. 1970;118:477–79.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics 2009. CA Cancer J Clin. 2009;59(2):225-49. https://doi.org/10.3322/caac.20006
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-17. https://doi.org/10.1002/ijc.25516
Abubaker K, Luwor RB, Escalona R, McNally O, Quinn MA, Thompson EW, et al. Targeted disruption of the JAK2/STAT3 pathway in combination with systemic administration of paclitaxel inhibits the priming of ovarian cancer stem cells leading to a reduced tumor burden. Front Oncol. 2014;4:75,1-12. https://doi.org/ 10.3389/fonc.2014.00075
Corvinus FM, Orth C, Moriggi R, Tsareva SA, Wagner S, Pfitzner EB, et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 2005;7(6):545-55. https://doi.org/10.1593/neo.04571
Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, et al. Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol. 2005;167(4):969-80. https://doi.org/10.1016/S0002-9440(10)61187-X
Aggarwal BB, Kunnumakkara AB, Harikumar KB, Gupta SR, Tharakan ST, Koca C, et al. Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci. 2009;1171:59-76. https://doi.org/ 10.1111/j.1749-6632.2009.04911.x
Podolak I, Galanty A, Sobolewska D. Saponins as cytotoxic agents: a review. Phytochem Rev. 2010;9(3):425-74. https://doi.org/10.1007/s11101-010-9183-z
Zhao M, Jiang B, Gao FH. Small molecule inhibitors of STAT3 for cancer therapy. Curr Med Chem. 2011;18(26):4012-18. https://doi.org/10.2174/092986711796957284
Bhattacharya SK, Satyan KS, Ghosal S. Antioxidant activity of glycowithanolides from Withania somnifera. Indian J Exp Biol. 1997;35(3):236-39. PMID: 9332168
Yang H, Shi G, Dou QP. The tumor proteasome is a primary target for the natural anticancer compound withaferin A isolated from "Indian winter cherry". Mol Pharmacol. 2007;71(2):426-37. https://doi.org/10.1124/mol.106.030015
Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 2011;32(11):1697-705. https://doi.org/10.1093/carcin/bgr192
Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papilloma virus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88:63–73. https://doi.org/ 10.1038/sj.bjc.6600688
Godefroy N, Lemaire C, Mignotte B, Vayssière JL. p53 and Retinoblastoma protein (pRb): a complex network of interactions. Apoptosis. 2006;11:659–61. https://doi.org/10.1007/s10495-006-5543-y
Scheffner M, Münger K, Byrne JC, and Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci. USA. 1991;88:5523–27. https://doi.org/10.1073/pnas.88.13.5523
Abdulkarim B, Sabri S, Deutsch E, Chagraoui H, Maggiorella L, Thierry J, et al. Antiviral agent Cidofovir restores p53 function and enhances the radiosensitivity in HPV-associated cancers. Oncogene. 2002;21:2334–46. https://doi.org/10.1038/sj.onc.1205006
Bossi G, Sacchi A. Restoration of wild-type p53 function in human cancer: relevance for tumor therapy. Head Neck. 2007;29(3):272–84. https://doi.org/10.1002/hed.20529
Goodwin EC, DiMaio D. Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc Natl Acad Sci. USA. 2000;97(23):12513–18. https://doi.org/10.1073/pnas.97.23.12513
Ravizza R, Gariboldi MB, Passarelli L, Monti E. Role of the p53/p21 system in the response of human colon carcinoma cells to Doxorubicin. BMC Cancer. 2004;4:92. https://doi.org/10.1186/1471-2407-4-92
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. https://doi.org/10.3322/caac.21166
Hunn J, Rodriguez GC. Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol. 2012;55(1):3–23. https://doi.org/ 10.1097/GRF.0b013e31824b4611
Matsuo K, Lin YG, Roman LD, Sood AK. Overcoming platinum resistance in ovarian carcinoma. Expert Opin Investig Drugs. 2010;19(11):1339–54. https://doi.org/10.1517/13543784.2010.515585
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3(7):730–37. https://doi.org/10.1038/nm0797-730
Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84. https://doi.org/10.1038/nrc1590
Hermann PC, Huber SL, Heeschen C. Metastatic cancer stem cells: a new target for anti-cancer therapy?. Cell Cycle. 2008;7(2):188–93. https://doi.org/10.4161/cc.7.2.5326
Kintzel PE. Anticancer drug-induced kidney disorders. Incidence, Prevention and Management. Drug Saf. 2001;24(1):19–38. https://doi.org/10.2165/00002018-200124010-00003
El-Awady ESE, Moustafa YM, Abo-Elmatty DM, Radwan A. Cisplatin induced cardiotoxicity: Mechanisms and cardioprotective strategies. Eur J Pharmacol. 2011;650:335–41. https://doi.org/ 10.1016/j.ejphar.2010.09.085
Lieberthal W, Triaca V, Levine J. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Am J Physiol. 1996;270(4):700–08. https://doi.org/10.1152/ajprenal.1996.270.4.F700
Kakar SS, Jala VR, Fong MY. Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem Biophys Res Commun. 2012;423:819–25. https://doi.org/10.1016/j.bbrc.2012.06.047
Lee TJ, Um HJ, Min DS, Park JW, Choi KS, Kwon TK. Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and downregulation of c-FLIP. Free Radic Biol Med. 2009;46:1639–49. https://doi.org/10.1016/j.freeradbiomed.2009.03.022
Parveen A, Parveen B, Parveen R, Ahmad S. Challenges and guidelines for clinical trial of herbal drugs. J Pharm Bioall Sci. 2015;7:329-33. https://doi.org/10.4103/0975-7406.168035
Manoharan S, Panjamurthy K, Pugalendi P, Balakrishnan S, Rajalingam K, Vellaichamy L, et al. Protective role of withaferin-A on red blood cell integrity during 7,12-dimethylbenz[A]anthracene induced oral carcinogenesis. Afr J Trad CAM. 2010;6(1):94-102. https://doi.org/10.4314/ajtcam.v6i1.57079
Panjamurthy K, Manoharan S, Nirmal MR, Vellaichamy L. Protective role of Withaferin-A on immunoexpression of p53 and bcl-2 in 7,12-dimethylbenz(a)anthracene-induced experimental oral carcinogenesis. Invest New Drugs. 2009;27:447–52. https://doi.org/10.1007/s10637-008-9199-z
Khazal KF, Hill DL, Grubbs CJ. Effect of Withania somnifera root extract on spontaneous estrogen receptor-negative mammary cancer in MMTV/Neu mice. Anticancer Res. 2014;34(11):6327–32. PMID: 25368231.
Hahm ER, Lee J, Kim SH, Sehrawat A, Arlotti JA, Shiva SS, Bhargava R, et al. Metabolic alterations in mammary cancer prevention by withaferin A in a clinically relevant mouse model. J Natl Cancer Inst. 2013;105:1111-22. https://doi.org/10.1093/jnci/djt153
Kim SH, Singh SV. Mammary cancer chemoprevention by withaferin A is accompanied by in vivo suppression of self-renewal of cancer stem cells. Cancer Prev Res. 2014;7(7):738–47. https://doi.org/10.1158/1940-6207.CAPR-13-0445
Nagalingam A, Kuppusamy P, Singh SV, Sharma D, Saxena NK. Mechanistic elucidation of the antitumor properties of withaferin A in breast cancer. Cancer Res. 2014;74:2617-29. https://doi.org/10.1158/0008-5472.CAN-13-2081
Gupta RC, Bansal SS, Aqil F, Jeyabalan J, Cao P, Kausar H, et al. Controlled-release systemic delivery - a new concept in cancer chemoprevention. Carcinogenesis. 2012;33(8):1608-15. https://doi.org/10.1093/carcin/bgs209
Singh N, Gilca M. Herbal Medicine – Science embraces tradition – a new insight into the ancient Ayurveda. Lambert Academic Publishing (Germany). 2010:51-67.
Singh N, Bhalla M, de Jager P, Gilca M. An Overview on Ashwagandha: A Rasayana (Rejuvenator) of Ayurveda. Afr J Tradit Complement Altern Med. 2011;8(S):208-13. https://doi.org/10.4314/ajtcam.v8i5S.9
Pires N, Gota V, Gulia A, Hingorani L, Agarwal M, Puri A. Safety and pharmacokinetics of Withaferin A in advanced stage high grade Osteosarcoma: A phase I trail. J Ayurveda Integr Med. 2019. https://doi.org/10.1016/j.jaim.2018.12.008
Wang HC, Tsai YL, Wu YC, Chang FR, Liu MH, Chen WY, et al. Withanolides-induced breast cancer cell death is correlated with their ability to inhibit heat protein 90. PLoS ONE. 2012;7(5):e37764.
Yin X, Yang G, Ma D, Su Z. Inhibition of cancer cell growth in cisplatin-resistant human oral cancer cells by withaferin-A is mediated via both apoptosis and autophagic cell death, endogenous ROS production, G2/M phase cell cycle arrest and by targeting MAPK/RAS/RAF signalling path. J BUON. 2020;25(1):332-37 PMID: 32277651.
Yu Y, Hamza A, Zhang T, Gu M, Zou P, Newman B, et al. Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochem. 2010;79(4):542-51. https://doi.org/10.1016/j.bcp.2009.09.017
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