Calpain and caspase orchestrated death signal to accomplish apoptosis induced by resveratrol and its novel analog hydroxystilbene-1 [correction of hydroxstilbene-1] in cancer cells

• Published in: The Journal of pharmacology and experimental therapeutics 2010-08, Vol.334 (2), p.381-394
• Main Authors: Guha, Prasun, Dey, Anindya, Dhyani, Manish V, Sen, Rupashree, Chatterjee, Mitali, Chattopadhyay, Subrata, Bandyopadhyay, Sandip K
• Format: Article
• Language: English
• Subjects: Anticarcinogenic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Calcium - metabolism; Calpain - physiology; Cardiolipins - metabolism; Caspases - physiology; Cell Line, Tumor; Cytochromes c - metabolism; Cytosol - metabolism; Humans; Membrane Potential, Mitochondrial - drug effects; Mitochondrial Membrane Transport Proteins - physiology; Reactive Oxygen Species - metabolism; Respiratory Burst; Signal Transduction; Stilbenes - pharmacology
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.167668

Stomach ulceration is a major side effect of most chemopreventive drugs. We have established that although resveratrol is a promising chemopreventive compound, it delays the ulcer healing process. However, its analog hydroxystilbene-1 (HST-1) was devoid of such an ulcerogenic side effect. Consequently, here we tried to explore the chemopreventive efficacy of HST-1 compared with resveratrol in different cancer cell lines and identified the probable signaling pathways responsible for cell death. Our cell viability study established that HST-1, compared with resveratrol, showed better chemopreventive potential in all of the cell lines tested, with U937 and MCF-7 being the cells most affected. Furthermore, in U937 and MCF-7 cell lines, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, cell cycle analysis, and nuclear fragmentation by confocal microscopy 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 Ca(2+) 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 in a caspase-independent but calpain-dependent manner as 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.