Molecular Targets and Mechanisms of Cancer Prevention and Treatment by Withaferin A, A Naturally Occurring Steroidal Lactone

Vyas, Avani R.; Singh, Shivendra V.

doi:10.1208/s12248-013-9531-1

Cited by 100 publications

(111 citation statements)

References 85 publications

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“…14,18,20,30 Accordingly we also found that WA treatment resulted in decreased expression of CDK1 but not cyclin B1 in both LY-10 and LY-3 cells lines, which may lead to G 2 /M phase arrest. Results of WA treatment on SudHL-6 cells were consistent with the G 2 /M phase arrest seen in melanoma, glioblastoma, and cervical cancer cells.…”

Section: Discussionsupporting

confidence: 60%

“…Other groups have published similar findings on the inhibition of Akt and have suggested that it may be a result of WA targeting the intermediate filament, Vimentin. 13,14 To determine if inhibition of vimentin function is important in DLBCL, we examined the effect of another inhibitor of vimentin, Arylquin 1, which is thought to bind vimentin and induce Par-4 dependent apoptosis. 42 We found that cytotoxicity required 10 fold higher concentration of Arylquin 1 in DLBCL than shown in mouse embryonic fibroblasts and PC-3 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…13 WA, the active compound found in the plant extract, shows promise to be a key anti-cancer therapeutic. 14 WA has been reported to inhibit proliferation and induce cell death in a variety of tumor models such as pancreatic, 15 breast, 16 lung, 17 cervical, 18 and prostate, 19 but its effects on DLBCL are not yet known.…”

Section: Introductionmentioning

confidence: 99%

“…14 Several studies found that WA stimulates apoptosis through restoring p53 levels and thus activating Bax and other pro-apoptotic Bcl-2 family proteins to induce apoptosis of cervical cancer cells, 18 or by enhancing levels of the proapoptotic factor, Par-4, and downstream caspase activation in prostate cancer cells. 19 In most cancer cell lines WA inhibits the proliferation of tumor cells through a G 2 /M phase cell cycle arrest, 20 and inhibits the activation of NF-kB via interaction with the IKKg subunit preventing IkB phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

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Anti-cancer activity of withaferin A in B-cell lymphoma

McKenna

Gachuki

Alhakeem

et al. 2015

Cancer Biology & Therapy

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Abbreviations: WA, Withaferin A; DLBCL, Diffuse large B cell lymphoma.Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-kB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-cancer activity of withaferin A in B-cell lymphoma

McKenna

Gachuki

Alhakeem

et al. 2015

Cancer Biology & Therapy

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“…19,20 WA targets the tumor proteasome, which leads to ubiquitinated protein accumulation and induction of ER stress in human cancer cells. 21,22 WA also has effects on autophagy, although the role of autophagy in the anticancer effects of WA remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Feng

Jiang

et al. 2016

Autophagy

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In contrast to normal tissue, cancer cells display profound alterations in protein synthesis and degradation. Therefore, proteins that regulate endoplasmic reticulum (ER) homeostasis are being increasingly recognized as potential therapeutic targets. The ubiquitin-proteasome system and autophagy are crucially important for proteostasis in cells. However, interactions between autophagy, the proteasome, and ER stress pathways in cancer remain largely undefined. This study demonstrated that withaferin-A (WA), the biologically active withanolide extracted from Withania somnifera, significantly increased autophagosomes, but blocked the degradation of autophagic cargo by inhibiting SNARE-mediated fusion of autophagosomes and lysosomes in human pancreatic cancer (PC) cells. WA specifically induced proteasome inhibition and promoted the accumulation of ubiquitinated proteins, which resulted in ER stress-mediated apoptosis. Meanwhile, the impaired autophagy at early stage induced by WA was likely activated in response to ER stress. Importantly, combining WA with a series of ER stress aggravators enhanced apoptosis synergistically. WA was well tolerated in mice, and displayed synergism with ER stress aggravators to inhibit tumor growth in PC xenografts. Taken together, these findings indicate that simultaneous suppression of 2 key intracellular protein degradation systems rendered PC cells vulnerable to ER stress, which may represent an avenue for new therapeutic combinations for this disease.

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Short-form RON overexpression augments benzyl isothiocyanate-induced apoptosis in human breast cancer cells

Sehrawat

Singh

2015

Mol. Carcinog.

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Chemoprevention of breast cancer is feasible with the use of non-toxic phytochemicals from edible and medicinal plants. Benzyl isothiocyanate (BITC) is one such plant compound that prevents mammary cancer development in a transgenic mouse model in association with tumor cell apoptosis. Prior studies from our laboratory have demonstrated a role for reactive oxygen species (ROS)-dependent Bax activation through the intermediary of c-Jun N-terminal kinases in BITC-induced apoptosis in human breast cancer cells. The present study demonstrates that truncated Recepteur d’Origine Nantais (sfRON) is a novel regulator of BITC-induced apoptosis in breast cancer cells. Overexpression of sfRON in MCF-7 and MDA-MB-361 cells resulted in augmentation of BITC-induced apoptosis when the apoptotic fraction was normalized against vehicle control for each cell type (untransfected and sfRON overexpressing cells). ROS generation and G2/M phase cell cycle arrest resulting from BITC treatment were significantly attenuated in sfRON overexpressing cells after normalization with vehicle control for each cell type. Increased BITC-induced apoptosis by sfRON overexpression was independent of c-Jun N-terminal kinase or p38 mitogen-activated protein kinase hyperphosphorylation. On the other hand, activation of Bax and Bak following BITC exposure was markedly more pronounced in sfRON overexpressing cells than in controls. sfRON overexpression also augmented apoptosis induction by structurally diverse cancer chemopreventive phytochemicals including withaferin A, phenethyl isothiocyanate, and D,L-sulforaphane. In conclusion, the present study provides novel mechanistic insights into the role of sfRON in apoptosis regulation by BITC and other electrophilic phytochemicals.

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Molecular Targets and Mechanisms of Cancer Prevention and Treatment by Withaferin A, A Naturally Occurring Steroidal Lactone

Cited by 100 publications

References 85 publications

Anti-cancer activity of withaferin A in B-cell lymphoma

Anti-cancer activity of withaferin A in B-cell lymphoma

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

Short-form RON overexpression augments benzyl isothiocyanate-induced apoptosis in human breast cancer cells

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