Molecular insight in the multifunctional activities of Withaferin A

Biochemical Pharmacology

Volumn 84, Issue 10, 2012, Pages 1282-1291

  Vanden Berghe, Wim ^a,b   Sabbe, Linde ^a   Kaileh, Mary ^c   Haegeman, Guy ^a   Heyninck, Karen ^a  

^a GHENT UNIVERSITY   (Belgium)

^b UNIVERSITY OF ANTWERP   (Belgium)

^c NATIONAL INSTITUTE ON AGING   (United States)

Author keywords

Angiogenesis; Carcinogenesis; Inflammation; Therapy; Withaferin A

Indexed keywords

IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PHOSPHOTRANSFERASE; PROTEASOME; WITHAFERIN A;

ANTIANGIOGENIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CELL CULTURE; CYTOSKELETON; DRUG ACTIVITY; DRUG STRUCTURE; ENZYME INHIBITION; HEALTH PROMOTION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; TRANSCRIPTION REGULATION;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL LINE, TUMOR; HEAT-SHOCK PROTEINS; HUMANS; NF-KAPPA B; PROTEASOME ENDOPEPTIDASE COMPLEX; PROTEIN KINASE INHIBITORS; TRANSCRIPTION, GENETIC; WITHANOLIDES;

EID: 84867851794     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2012.08.027     Document Type: Review

References (116)

1. J.W. Moncrief, and K.S. Heller Acylation: a proposed mechanism of action for various oncolytic agents based on model chemical systems Cancer Res 27 1967 1500 1502
2. S. Santagata, Y.M. Xu, E.M. Wijeratne, R. Kontnik, C. Rooney, and C.C. Perley Using the heat-shock response to discover anticancer compounds that target protein homeostasis ACS Chem Biol 7 2011 340 349
3. L. Misra, P. Lal, N.D. Chaurasia, R.S. Sangwan, S. Sinha, and R. Tuli Selective reactivity of 2-mercaptoethanol with 5beta,6beta-epoxide in steroids from Withania somnifera Steroids 73 2008 245 251
4. M. Kaileh, W. Vanden Berghe, A. Heyerick, J. Horion, J. Piette, and C. Libert Withaferin A strongly elicits IkappaB kinase beta hyperphosphorylation concomitant with potent inhibition of its kinase activity J Biol Chem 282 2007 4253 4264
5. W. Suttana, S. Mankhetkorn, W. Poompimon, A. Palagani, S. Zhokhov, and S. Gerlo Differential chemosensitization of P-glycoprotein overexpressing K562/Adr cells by withaferin A and Siamois polyphenols Mol Cancer 9 2010 99
6. R.R. Falsey, M.T. Marron, G.M. Gunaherath, N. Shirahatti, D. Mahadevan, and A.A. Gunatilaka Actin microfilament aggregation induced by withaferin A is mediated by annexin II Nat Chem Biol 2 2006 33 38
7. P. Bargagna-Mohan, A. Hamza, Y.E. Kim, Y. Khuan Abby Ho, N. Mor-Vaknin, and N. Wendschlag The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin Chem Biol 14 2007 623 634
8. Y. Yokota, P. Bargagna-Mohan, P.P. Ravindranath, K.B. Kim, and R. Mohan Development of withaferin A analogs as probes of angiogenesis Bioorg Med Chem Lett 16 2006 2603 2607
9. P. Bargagna-Mohan, R.R. Paranthan, A. Hamza, N. Dimova, B. Trucchi, and C. Srinivasan Withaferin A targets intermediate filaments glial fibrillary acidic protein and vimentin in a model of retinal gliosis J Biol Chem 285 2010 7657 7669
10. P. Bargagna-Mohan, R.R. Paranthan, A. Hamza, C.G. Zhan, D.M. Lee, and K.B. Kim Corneal antifibrotic switch identified in genetic and pharmacological deficiency of vimentin J Biol Chem 287 2012 989 1006
11. B. Grin, S. Mahammad, T. Wedig, M.M. Cleland, L. Tsai, and H. Herrmann Withaferin a alters intermediate filament organization, cell shape and behavior PLoS ONE 7 2012 e39065
12. R.R. Paranthan, P. Bargagna-Mohan, D.L. Lau, and R. Mohan A robust model for simultaneously inducing corneal neovascularization and retinal gliosis in the mouse eye Mol Vis 17 2011 1901 1908
13. J. Ivaska, H.M. Pallari, J. Nevo, and J.E. Eriksson Novel functions of vimentin in cell adhesion, migration, and signaling Exp Cell Res 313 2007 2050 2062
14. J. Ivaska, K. Vuoriluoto, T. Huovinen, I. Izawa, M. Inagaki, and P.J. Parker PKCepsilon-mediated phosphorylation of vimentin controls integrin recycling and motility EMBO J 24 2005 3834 3845
15. P. Janosch, A. Kieser, M. Eulitz, J. Lovric, G. Sauer, and M. Reichert The Raf-1 kinase associates with vimentin kinases and regulates the structure of vimentin filaments FASEB J 14 2000 2008 2021
16. E. Perlson, I. Michaelevski, N. Kowalsman, K. Ben-Yaakov, M. Shaked, and R. Seger Vimentin binding to phosphorylated Erk sterically hinders enzymatic dephosphorylation of the kinase J Mol Biol 364 2006 938 944
17. W.C. Sin, X.Q. Chen, T. Leung, and L. Lim RhoA-binding kinase alpha translocation is facilitated by the collapse of the vimentin intermediate filament network Mol Cell Biol 18 1998 6325 6339
18. J. Satoh, T. Yamamura, and K. Arima The 14-3-3 protein epsilon isoform expressed in reactive astrocytes in demyelinating lesions of multiple sclerosis binds to vimentin and glial fibrillary acidic protein in cultured human astrocytes Am J Pathol 165 2004 577 592
19. G. Tzivion, Z.J. Luo, and J. Avruch Calyculin A-induced vimentin phosphorylation sequesters 14-3-3 and displaces other 14-3-3 partners in vivo J Biol Chem 275 2000 29772 29778
20. M.H. Zhang, J.S. Lee, H.J. Kim, D.I. Jin, J.I. Kim, and K.J. Lee HSP90 protects apoptotic cleavage of vimentin in geldanamycin-induced apoptosis Mol Cell Biochem 281 2006 111 121
21. A. Satelli, and S. Li Vimentin in cancer and its potential as a molecular target for cancer therapy Cell Mol Life Sci 68 2011 3033 3046
22. R. Mohan, H.J. Hammers, P. Bargagna-Mohan, X.H. Zhan, C.J. Herbstritt, and A. Ruiz Withaferin A is a potent inhibitor of angiogenesis Angiogenesis 7 2004 115 122
23. G. Lahat, Q.S. Zhu, K.L. Huang, S. Wang, S. Bolshakov, and J. Liu Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies PLoS ONE 5 2010 e10105
24. Y. Byun, F. Chen, R. Chang, M. Trivedi, K.J. Green, and V.L. Cryns Caspase cleavage of vimentin disrupts intermediate filaments and promotes apoptosis Cell Death Differ 8 2001 443 450
25. F. Chi, T.D. Jong, L. Wang, Y. Ouyang, C. Wu, and W. Li Vimentin-mediated signalling is required for IbeA+ E. coli K1 invasion of human brain microvascular endothelial cells Biochem J 427 2010 79 90
26. X. Che, F. Chi, L. Wang, T.D. Jong, C.H. Wu, and X. Wang Involvement of IbeA in meningitic Escherichia coli K1-induced polymorphonuclear leukocyte transmigration across brain endothelial cells Brain Pathol 21 2011 389 404
27. J.T. Thaiparambil, L. Bender, T. Ganesh, E. Kline, P. Patel, and Y. Liu Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation Int J Cancer 129 2011 2744 2755
28. Q.F. Li, A.M. Spinelli, R. Wang, Y. Anfinogenova, H.A. Singer, and D.D. Tang Critical role of vimentin phosphorylation at Ser-56 by p21-activated kinase in vimentin cytoskeleton signaling J Biol Chem 281 2006 34716 34724
29. J.F. Caplan, N.R. Filipenko, S.L. Fitzpatrick, and D.M. Waisman Regulation of annexin A2 by reversible glutathionylation J Biol Chem 279 2004 7740 7750
30. D. Chen, K.G. Daniel, M.S. Chen, D.J. Kuhn, K.R. Landis-Piwowar, and Q.P. Dou Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells Biochem Pharmacol 69 2005 1421 1432
31. H. Yang, G. Shi, and Q.P. Dou The tumor proteasome is a primary target for the natural anticancer compound Withaferin A isolated from Indian winter cherry Mol Pharmacol 71 2007 426 437
32. A. Grover, A. Shandilya, V.S. Bisaria, and D. Sundar Probing the anticancer mechanism of prospective herbal drug Withaferin A on mammals: a case study on human and bovine proteasomes BMC Genomics 11 Suppl. 4 2010 S15
33. X. Zhang, R. Mukerji, A.K. Samadi, and M.S. Cohen 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 11 2011 84
34. A. Grover, A. Shandilya, A. Punetha, V.S. Bisaria, and D. Sundar Inhibition of the NEMO/IKKbeta association complex formation, a novel mechanism associated with the NF-kappaB activation suppression by Withania somnifera's key metabolite withaferin A BMC Genomics 11 Suppl. 4 2010 S25
35. M. Bernier, Y.K. Kwon, S.K. Pandey, T.N. Zhu, R.J. Zhao, and A. Maciuk Binding of manumycin A inhibits IkappaB kinase beta activity J Biol Chem 281 2006 2551 2561
36. S.C. Gupta, S. Prasad, S. Reuter, R. Kannappan, V.R. Yadav, and J. Ravindran Modification of cysteine 179 of IkappaBalpha 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 285 2010 35406 35417
37. B.H. Kim, J.Y. Lee, J.H. Seo, H.Y. Lee, S.Y. Ryu, and B.W. Ahn Artemisolide is a typical inhibitor of IkappaB kinase beta targeting cysteine-179 residue and down-regulates NF-kappaB-dependent TNF-alpha expression in LPS-activated macrophages Biochem Biophys Res Commun 361 2007 593 598
38. M.C. Liang, S. Bardhan, E.A. Pace, D. Rosman, J.A. Beutler, and J.A. Porco Jr. Inhibition of transcription factor NF-kappaB signaling proteins IKKbeta and p65 through specific cysteine residues by epoxyquinone A monomer: correlation with its anti-cancer cell growth activity Biochem Pharmacol 71 2006 634 645
39. U.D. Palempalli, U. Gandhi, P. Kalantari, H. Vunta, R.J. Arner, and V. Narayan Gambogic acid covalently modifies IkappaB kinase-beta subunit to mediate suppression of lipopolysaccharide-induced activation of NF-kappaB in macrophages Biochem J 419 2009 401 409
40. R. Maitra, M.A. Porter, S. Huang, and B.P. Gilmour Inhibition of NFkappaB by the natural product Withaferin A in cellular models of Cystic Fibrosis inflammation J Inflamm (Lond) 6 2009 15
41. E.P. Sabina, S. Chandal, and M.K. Rasool Inhibition of monosodium urate crystal-induced inflammation by withaferin A J Pharm Pharm Sci 11 2008 46 55
42. N. Sen, B. Banerjee, B.B. Das, A. Ganguly, T. Sen, and S. Pramanik Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex Cell Death Differ 14 2007 358 367
43. J.H. Oh, T.J. Lee, S.H. Kim, Y.H. Choi, S.H. Lee, and J.M. Lee Induction of apoptosis by withaferin A in human leukemia U937 cells through down-regulation of Akt phosphorylation Apoptosis 13 2008 1494 1504
44. C. Mandal, A. Dutta, A. Mallick, S. Chandra, L. Misra, and R.S. Sangwan 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 13 2008 1450 1464
45. X. Zhang, A.K. Samadi, K.F. Roby, B. Timmermann, and M.S. Cohen Inhibition of cell growth and induction of apoptosis in ovarian carcinoma cell lines CaOV3 and SKOV3 by natural withanolide Withaferin A Gynecol Oncol 124 2012 606 612
46. J.H. Oh, and T.K. Kwon Withaferin A inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules by inactivation of Akt and NF-kappaB in human pulmonary epithelial cells Int Immunopharmacol 9 2009 614 619
47. J.H. Oh, T.J. Lee, J.W. Park, and T.K. Kwon Withaferin A inhibits iNOS expression and nitric oxide production by Akt inactivation and down-regulating LPS-induced activity of NF-kappaB in RAW 264.7 cells Eur J Pharmacol 599 2008 11 17
48. A. Grover, A. Shandilya, V. Agrawal, P. Pratik, D. Bhasme, and V.S. Bisaria Blocking the chaperone kinome pathway: mechanistic insights into a novel dual inhibition approach for supra-additive suppression of malignant tumors Biochem Biophys Res Commun 404 2010 498 503
49. A. Grover, A. Shandilya, V. Agrawal, P. Pratik, D. Bhasme, and V.S. Bisaria Hsp90/Cdc37 chaperone/co-chaperone complex, a novel junction anticancer target elucidated by the mode of action of herbal drug Withaferin A BMC Bioinformatics 12 Suppl. 1 2011 S30
50. Y. Yu, A. Hamza, T. Zhang, M. Gu, P. Zou, and B. Newman Withaferin A targets heat shock protein 90 in pancreatic cancer cells Biochem Pharmacol 79 2010 542 551
51. L.M. Karnitz, and S.J. Felts Cdc37 regulation of the kinome: when to hold 'em and when to fold' em Sci STKE 2007 2007 pe22
52. T. Bouwmeester, A. Bauch, H. Ruffner, P.O. Angrand, G. Bergamini, and K. Croughton A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway Nat Cell Biol 6 2004 97 105
53. G. Chen, P. Cao, and D.V. Goeddel TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90 Mol Cell 9 2002 401 410
54. L. Stepanova, X. Leng, S.B. Parker, and J.W. Harper Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4 Genes Dev 10 1996 1491 1502
55. A.D. Basso, D.B. Solit, G. Chiosis, B. Giri, P. Tsichlis, and N. Rosen Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function J Biol Chem 277 2002 39858 39866
56. H.C. Wang, Y.L. Tsai, Y.C. Wu, F.R. Chang, M.H. Liu, and W.Y. Chen Withanolides-induced breast cancer cell death is correlated with their ability to inhibit heat protein 90 PLoS ONE 7 2012 e37764
57. M.L. Mendillo, S. Santagata, M. Koeva, G.W. Bell, R. Hu, and R.M. Tamimi HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers Cell 150 2012 549 562
58. J. Zou, Y. Guo, T. Guettouche, D.F. Smith, and R. Voellmy Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1 Cell 94 1998 471 480
59. A. Mehrotra, D. Kaul, and K. Joshi LXR-alpha selectively reprogrammes cancer cells to enter into apoptosis Mol Cell Biochem 349 2011 41 55
60. V.P. Dave, D. Kaul, Y. Sharma, and R. Bhattacharya Functional genomics of blood cellular LXR-alpha gene in human coronary heart disease J Mol Cell Cardiol 46 2009 536 544
61. K.J. Min, K. Choi, and T.K. Kwon Withaferin A down-regulates lipopolysaccharide-induced cyclooxygenase-2 expression and PGE2 production through the inhibition of STAT1/3 activation in microglial cells Int Immunopharmacol 11 2011 1137 1142
62. J. Lee, E.R. Hahm, and S.V. Singh Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells Carcinogenesis 31 2010 1991 1998
63. R. Munagala, H. Kausar, C. Munjal, and R.C. Gupta Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells Carcinogenesis 32 2011 1697 1705
64. S. Koduru, R. Kumar, S. Srinivasan, M.B. Evers, and C. Damodaran Notch-1 inhibition by Withaferin-A: a therapeutic target against colon carcinogenesis Mol Cancer Ther 9 2010 202 210
65. M.N. Ndlovu, C. Van Lint, K. Van Wesemael, P. Callebert, D. Chalbos, and G. Haegeman Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells Mol Cell Biol 29 2009 5488 5504
66. S.D. Stan, E.R. Hahm, R. Warin, and S.V. Singh Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo Cancer Res 68 2008 7661 7669
67. F. Blaschke, O. Leppanen, Y. Takata, E. Caglayan, J. Liu, and M.C. Fishbein Liver X receptor agonists suppress vascular smooth muscle cell proliferation and inhibit neointima formation in balloon-injured rat carotid arteries Circ Res 95 2004 e110 e123
68. L.L. Vedin, S.A. Lewandowski, P. Parini, J.A. Gustafsson, and K.R. Steffensen The oxysterol receptor LXR inhibits proliferation of human breast cancer cells Carcinogenesis 30 2009 575 579
69. S.B. Joseph, A. Castrillo, B.A. Laffitte, D.J. Mangelsdorf, and P. Tontonoz Reciprocal regulation of inflammation and lipid metabolism by liver X receptors Nat Med 9 2003 213 219
70. N. Zelcer, and Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling J Clin Invest 116 2006 607 614
71. M.I. Choudhary, S. Yousuf, S.A. Nawaz, S. Ahmed, and Atta-ur-Rahman Cholinesterase inhibiting withanolides from Withania somnifera Chem Pharm Bull (Tokyo) 52 2004 1358 1361
72. R. Schliebs, A. Liebmann, S.K. Bhattacharya, A. Kumar, S. Ghosal, and V. Bigl Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain Neurochem Int 30 1997 181 190
73. A.K. Samadi, R. Mukerji, A. Shah, B.N. Timmermann, and M.S. Cohen A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo Surgery 148 2010 1228 1236 [discussion 36]
74. R.C. Gupta, S. Bansal, F. Aqil, J. Jeyabalan, P. Cao, and H. Kausar Controlled-release systemic delivery - a new concept in cancer chemoprevention Carcinogenesis 33 2012 1608 1615
75. S. Manoharan, K. Panjamurthy, S. Balakrishnan, K. Vasudevan, and L. Vellaichamy Circadian time-dependent chemopreventive potential of withaferin-A in 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis Pharmacol Rep 61 2009 719 726
76. K. Panjamurthy, S. Manoharan, V.P. Menon, M.R. Nirmal, and N. Senthil Protective role of withaferin-A on 7,12-dimethylbenz(a)anthracene-induced genotoxicity in bone marrow of Syrian golden hamsters J Biochem Mol Toxicol 22 2008 251 258
77. K. Panjamurthy, S. Manoharan, M.R. Nirmal, and L. Vellaichamy 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 27 2009 447 452
78. N. Widodo, N. Shah, D. Priyandoko, T. Ishii, S.C. Kaul, and R. Wadhwa Deceleration of senescence in normal human fibroblasts by withanone extracted from ashwagandha leaves J Gerontol A: Biol Sci Med Sci 64 2009 1031 1038
79. A. Samadi, P. Loo, R. Mukerji, G. O'Donnell, X. Tong, and B.N. Timmermann A novel HSP90 modulator with selective activity against thyroid cancers in vitro Surgery 146 2009 1196 1207
80. N. Widodo, D. Priyandoko, N. Shah, R. Wadhwa, and S.C. Kaul Selective killing of cancer cells by Ashwagandha leaf extract and its component Withanone involves ROS signaling PLoS ONE 5 2010 e13536
81. P.U. Devi, K. Akagi, V. Ostapenko, Y. Tanaka, and T. Sugahara Withaferin A: a new radiosensitizer from the Indian medicinal plant Withania somnifera Int J Radiat Biol 69 1996 193 197
82. P.U. Devi, and R. Kamath Radiosensitizing effect of withaferin A combined with hyperthermia on mouse fibrosarcoma and melanoma J Radiat Res (Tokyo) 44 2003 1 6
83. P.U. Devi, R. Kamath, and B.S. Rao Radiosensitization of a mouse melanoma by withaferin A: in vivo studies Indian J Exp Biol 38 2000 432 437
84. P.U. Devi, A.C. Sharada, and F.E. Solomon In vivo growth inhibitory and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma Cancer Lett 95 1995 189 193
85. G. Kalthur, and U.D. Pathirissery Enhancement of the response of B16F1 melanoma to fractionated radiotherapy and prolongation of survival by withaferin A and/or hyperthermia Integr Cancer Ther 9 2010 370 377
86. A.C. Sharada, F.E. Solomon, P.U. Devi, N. Udupa, and K.K. Srinivasan Antitumor and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma in vivo Acta Oncol 35 1996 95 100
87. E.S. Yang, M.J. Choi, J.H. Kim, K.S. Choi, and T.K. Kwon Combination of withaferin A and X-ray irradiation enhances apoptosis in U937 cells Toxicol In Vitro 25 2011 1803 1810
88. S.S. Kakar, V.R. Jala, and M.Y. Fong Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines Biochem Biophys Res Commun 423 2012 819 825
89. A. Ganasoundari, S.M. Zare, and P.U. Devi Modification of bone marrow radiosensensitivity by medicinal plant extracts Br J Radiol 70 1997 599 602
90. N. Shah, H. Kataria, S.C. Kaul, T. Ishii, G. Kaur, and R. Wadhwa 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 100 2009 1740 1747
91. M. Rasool, and P. Varalakshmi Suppressive effect of Withania somnifera root powder on experimental gouty arthritis: an in vivo and in vitro study Chem Biol Interact 164 2006 174 180
92. U. Minhas, R. Minz, and A. Bhatnagar Prophylactic effect of Withania somnifera on inflammation in a non-autoimmune prone murine model of lupus Drug Discov Ther 5 2012 195 201
93. V. Swarup, D. Phaneuf, N. Dupre, S. Petri, M. Strong, and J. Kriz Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways J Exp Med 208 2011 2429 2447
94. D.J. Newman, G.M. Cragg, and K.M. Snader Natural products as sources of new drugs over the period 1981-2002 J Nat Prod 66 2003 1022 1037
95. D. Singh, A. Aggarwal, R. Maurya, and S. Naik Withania somnifera inhibits NF-kappaB and AP-1 transcription factors in human peripheral blood and synovial fluid mononuclear cells Phytother Res 21 2007 905 913
96. H. Peng, G. Olsen, Y. Tamura, H. Noguchi, S. Matsumoto, and M.F. Levy Inhibition of inflammatory cytokine-induced response in human islet cells by withaferin A Transplant Proc 42 2010 2058 2061
97. N. Malara, D. Foca, F. Casadonte, M.F. Sesto, L. Macrina, and L. Santoro Simultaneous inhibition of the constitutively activated nuclear factor kappaB and of the interleukin-6 pathways is necessary and sufficient to completely overcome apoptosis resistance of human U266 myeloma cells Cell Cycle 7 2008 3235 3245
98. S. Srinivasan, R.S. Ranga, R. Burikhanov, S.S. Han, and D. Chendil Par-4-dependent apoptosis by the dietary compound withaferin A in prostate cancer cells Cancer Res 67 2007 246 253
99. H. Ichikawa, Y. Takada, S. Shishodia, B. Jayaprakasam, M.G. Nair, and B.B. Aggarwal Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NF-kappaB) activation and NF-kappaB-regulated gene expression Mol Cancer Ther 5 2006 1434 1445
100. F. Malik, A. Kumar, S. Bhushan, S. Khan, A. Bhatia, and K.A. Suri Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine Apoptosis 12 2007 2115 2133
101. W. Peschel, A. Kump, and J.M. Prieto Effects of 20-hydroxyecdysone, Leuzea carthamoides extracts, dexamethasone and their combinations on the NF-kappaB activation in HeLa cells J Pharm Pharmacol 63 2011 1483 1495
102. W. Lee, T.H. Kim, S.K. Ku, K.J. Min, H.S. Lee, and T.K. Kwon Barrier protective effects of withaferin A in HMGB1-induced inflammatory responses in both cellular and animal models Toxicol Appl Pharmacol 262 2012 91 98
103. C. Stevens, P. Henderson, E.R. Nimmo, D.C. Soares, B. Dogan, and K.W. Simpson The intermediate filament protein, vimentin, is a regulator of NOD2 activity Gut 2012 PMID: 22684479
104. A. Franchitto, A. Torrice, R. Semeraro, C. Napoli, G. Nuzzo, and F. Giuliante Prostate apoptosis response-4 is expressed in normal cholangiocytes, is down-regulated in human cholangiocarcinoma, and promotes apoptosis of neoplastic cholangiocytes when induced pharmacologically Am J Pathol 177 2010 1779 1790
105. M.I. Choudhary, S. Hussain, S. Yousuf, A. Dar, Mudassar, and Atta-ur-Rahman Chlorinated and diepoxy withanolides from Withania somnifera and their cytotoxic effects against human lung cancer cell line Phytochemistry 71 2010 2205 2209
106. M.J. Choi, E.J. Park, K.J. Min, J.W. Park, and T.K. Kwon Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells Toxicol In Vitro 25 2011 692 698
107. E.R. Hahm, J. Lee, Y. Huang, and S.V. Singh Withaferin a suppresses estrogen receptor-alpha expression in human breast cancer cells Mol Carcinog 50 2011 614 624
108. E.R. Hahm, M.B. Moura, E.E. Kelley, B. Van Houten, S. Shiva, and S.V. Singh Withaferin A-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species PLoS ONE 6 2011 e23354
109. E. Mayola, C. Gallerne, D.D. Esposti, C. Martel, S. Pervaiz, and L. Larue Withaferin A induces apoptosis in human melanoma cells through generation of reactive oxygen species and down-regulation of Bcl-2 Apoptosis 16 2011 1014 1027
110. T.J. Lee, H.J. Um, S. Min do, J.W. Park, K.S. Choi, and T.K. Kwon Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP Free Radic Biol Med 46 2009 1639 1649
111. X. Liu, W. Qi, L.S. Cooke, E.M. Kithsiri Wijeratne, Y.M. Xu, and M.T. Marron An analog of withaferin A activates the MAPK and glutathione stress pathways and inhibits pancreatic cancer cell proliferation Cancer Invest 29 2011 668 675
112. G.G. Llanos, L.M. Araujo, I.A. Jiménez, L.M. Moujir, and I.L. Bazzocchi Withaferin A-related steroids from Withania aristata exhibit potent antiproliferative activity by inducing apoptosis in human tumor cells Eur J Med Chem. 54 2012 499 511
113. P. Bargagna-Mohan, P.P. Ravindranath, and R. Mohan Small molecule anti-angiogenic probes of the ubiquitin proteasome pathway: potential application to choroidal neovascularization Invest Ophthalmol Vis Sci 47 2006 4138 4145
114. S.D. Stan, Y. Zeng, and S.V. Singh Ayurvedic medicine constituent withaferin a causes G2 and M phase cell cycle arrest in human breast cancer cells Nutr Cancer 60 Suppl. 1 2008 51 60
115. B. Jayaprakasam, Y. Zhang, N.P. Seeram, and M.G. Nair Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves Life Sci 74 2003 125 132
116. M.Y. Fong, S. Jin, M. Rane, R.K. Singh, R. Gupta, and S.S. Kakar Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer PLoS ONE 7 2012 e42265