Apoptosis induced by capsaicin and resveratrol in colon carcinoma cells requires nitric oxide production and caspase activation.
Although many studies have focused on anticarcinogenic properties of capsaicin and resveratrol, molecular mechanisms by which they selectively induce apoptosis are incompletely characterized. We examined the role of nitric oxide (NO) and influence of p53 status during apoptosis induced by these agents in two isogenic HCT116 human colon carcinomas, wild-type p53 (p53-WT) and complete knockout of p53 (p53-null) cells. Capsaicin and resveratrol, alone or in combination, inhibited cell growth and promoted apoptosis by the elevation of NO; combined treatment in p53-WT cells was most effective. Increased NO production after treatment uniformly stimulated p53 and Bax expression through Mdm2 down-regulation in p53-WT cells, whereas all were unaffected in p53-null cells. Both cell types underwent a reduction in the levels of anti-apoptotic Bcl-2 protein, cytochrome c loss from mitochondria and activation of caspase 9 together with caspase 3, independently of p53 status. Concomitantly, we observed DR4, Fas(CD95) and caspase 8 activation, suggesting that these compounds activate both the mitochondrial and death receptor pathways working together to induce apoptosis. These findings provide insight into the mechanism of apoptotic action of capsaicin and resveratrol based on p53 status and indicate manipulation of NO may offer exciting opportunities to improve the effectiveness of colon cancer treatment.
Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Min Young
MY
Kim
Laura J
LJ
Trudel
Gerald N
GN
Wogan
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D007527:Isoenzymes; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D019323:omega-N-Methylarginine
D000972:Antineoplastic Agents, Phytogenic; D001120:Arginine; D002211:Capsaicin; D053148:Caspase 3; D053453:Caspase 9; D045304:Cytochromes c; D007527:Isoenzymes; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009707:Nucleosomes; D000077185:Resveratrol; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C092506:N(G)-monomethylarginine acetate; D019323:omega-N-Methylarginine; C495901:TP53 protein, human