Calpain and caspase orchestrated death signal to accomplish apoptosis induced by resveratrol and its novel analog HST‐1 in cancer cells

Stomach ulceration is a major side effect of most chemopreventive drugs. We have established resveratrol delays the ulcer healing process. However, its analog HST‐1 was devoid of such side effect. We showed the chemopreventive efficacy of HST‐1 compared with resveratrol in different cancer cells and identified the probable signaling pathways responsible for cell death. Cell viability study established that HST‐1, compared with resveratrol, showed better chemopreventive potential in the entire cell lines tested, with U937 and MCF‐7 being the cells most affected. Furthermore, in U937 and MCF‐7 cell lines, TUNEL assay, cell cycle analysis, and nuclear fragmentation established that both HST‐1 and resveratrol switched on the apoptotic death cascade to execute cell death. The initiator signal was Fas‐independent but synchronized in terms of cytosolic Calcium influx, dissipation of mitochondrial membrane potential, and oxidative burst. It is noteworthy that the executioner signal was cell‐specific as in U937 cells; HST‐1 and resveratrol treatment induced mitochondrial permealization followed by cardiolipin depletion and cytochrome c release, which eventually activated downstream caspases 9 and 3 to execute the death process. In contrast, in MCF‐7 cells the death process was executed as caspase‐independent but calpain dependent. Calpain activation induced cleavage of cytosolic alpha‐fodrin, stimulated mitochondrial release of apoptotic inducing factor and endonuclease G and thus harmonized cytosolic and mitochondrial death signals to accomplish apoptosis.