ABSTRACT
Mouse sarcoma 180 solid and ascites tumor cells were treated in vivo and in vitro with withaferin A. It was found to affect the spindle microtubules of cells in metaphase. P388 cells, 4-dehydrowithaferin A and withaferin A diacetate exhibited an equal inhibitory effect on thymidine, uridine, and L-valine incorporation. They stopped cell proliferation and, at the same time, killed the cells. Withaferin A promptly reacted with L-cysteine, and it was presumed that possible target sites in the cell might be the SH groups of enzymes which react with the lactone and epoxide groups of the agent. Withaferin A potently inhibits the chymotrypsin-like activity of a purified rabbit 20S proteasome and 26S proteasome in human prostate cancer cultures. Withaferin A induced Par-4-dependent apoptosis in androgen-refractory prostate cancer cells and regression of PC-3 xenografts in nude mice. Withaferin A primarily induces oxidative stress in human leukemia HL-60 cells and in several other cancer cell lines.
