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

Abstract

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.

Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression

“…To the best of our knowledge, only a few reports indicate that WA has no significant effect on normal tissue, and there are no reports describing its effects on normal hematopoietic cells. We therefore compared the growth‐suppressive effects of WA among human normal bone marrow CD34‐positive cells, MDS‐L cells and MDS92 cells.…”

“…Previous reports have demonstrated that WA affects microtubules or vimentin intermediate filaments and, subsequently, exerts cytotoxicity or inhibition of the epithelial–mesenchymal transition . WA is reported to induce cell cycle arrest at G2/M phase, resulting in apoptosis . Nonetheless, the detailed mechanisms of action remain to be determined and may be different depending on the cells, tissues or experimental systems.…”

“…(7)(8)(9)(10) WA is reported to induce cell cycle arrest at G2/M phase, resulting in apoptosis. (8,(11)(12)(13)(14)(15) Nonetheless, the detailed mechanisms of action remain to be determined and may be different depending on the cells, tissues or experimental systems.…”

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“…WFA ( Figure 1A), a member of a large group of compounds collectively called withanolides was first isolated [26] from the alcoholic extracts of the Indian Ayurvedic medicinal herb, Withania somnifera (Ashwagandha). In the past decade, WFA has been widely investigated in preclinical studies [27] for its antitumor activity against lung [28][29][30][31], breast [32][33][34], uterine and cervix [35], ovarian [36], pancreatic [37], B-cell lymphoma [38]. Attractively, recently published studies [36,39,40] have demonstrated that subcytotoxic concentrations of WFA synergize the efficacy of standard chemotherapeutic drugs.…”

Withaferin a synergistically enhances the effects of paclitaxel against lung cancer.

“…Over the past decade or so, preclinical data has accumulated indicating the potency and efficacy of WFA against various cancer cell types. A review of the literature shows that several studies have been published demonstrating the in vitro and in vivo efficacy of WFA against the proliferation of various cancer cell types [37,39,[65][66][67]. More importantly, the evidence is now accumulating indicating the potential of WFA to synergize the anticancer activity of standard chemotherapeutic drugs like cisplatin and carboplatin against ovarian and breast cancers [40].…”