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The practitioners of the traditional Indian system of medicine regard Withania somnifera Dun. as the 'Indian ginseng'. A new withanolide-free aqueous fraction was isolated from the roots of this plant and was evaluated for putative antistress activity against a battery of tests such as hypoxia time, antifatigue effect, swimming performance time, swimming induced gastric ulceration and hypothermia, immobilization induced gastric ulceration, autoanalgesia and biochemical changes in the adrenal glands. This bioactive fraction exhibited significant antistress activity in a dose-related manner in all the parameters studied. The extract of Withania somnifera root (a commercial preparation available locally) was used to compare the results. A preliminary acute toxicity study in mice showed a good margin of safety.

Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1a/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1a, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G 1 -S transitionphase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent. Cancer Res; 75(14); 2886-96. Ó2015 AACR.

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