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.
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.
Guha
Prasun
P
Department of Biochemistry, Dr B C Roy Postgraduate Institute of Basic Medical Sciences and Institute of Post-Graduate Medical Education and Research, 244B, Acharya Jagadish Chandra Bose Road, Kolkata 700-020, India.
Dey
Anindya
A
Dhyani
Manish V
MV
Sen
Rupashree
R
Chatterjee
Mitali
M
Chattopadhyay
Subrata
S
Bandyopadhyay
Sandip K
SK
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000502:physiology*; D002308:Cardiolipins / Q000378:metabolism; D020169:Caspases / Q000502:physiology*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*
C551466:3,3',5,5'-tetrahydroxystilbene; D016588:Anticarcinogenic Agents; D002308:Cardiolipins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D013267:Stilbenes; D045304:Cytochromes c; D002154:Calpain; D020169:Caspases; D000077185:Resveratrol; D002118:Calcium