Combined application of camptothecin and the guanylate cyclase activator YC-1: Impact on cell death and apoptosis-related proteins in ovarian carcinoma cell lines.
Camptothecin analogs and guanylate cyclase activator YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] have been shown to induce apoptosis in cancer cells. However, the combined effect of camptothecin analogs and YC-1 on the viability of epithelial ovarian cancer cells remains uncertain. We assessed the combined effect of YC-1 on the camptothecin toxicity in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Camptothecin and YC-1 induced apoptosis in OVCAR-3 and SK-OV-3 cells in a dose- and time-dependent manner. Both compounds induced nuclear damage, decreased Bid and Bcl-2 protein levels, enhanced cytochrome c release, activated caspase-3 and upregulated tumor suppressor p53. Camptothecin decreased Bax protein levels, whereas YC-1 increased Bax levels. YC-1 enhanced the camptothecin-induced changes in the apoptotic protein levels and increased apoptotic effect of camptothecin on ovarian carcinoma cell lines. The results suggested that YC-1 may enhance a camptothecin toxicity against ovarian carcinoma cell lines by increasing activation of the caspase-8 and Bid pathway as well as activation of the mitochondria-mediated apoptotic pathway, leading to cytochrome c release and subsequent caspase-3 activation. Combination of camptothecin analogs and YC-1 may provide a therapeutic benefit against ovarian adenocarcinoma.
Lee
Sun-Joo
SJ
Department of Obstetrics and Gynecology, Konkuk University Hospital, Konkuk University, Seoul, South Korea.
Kim
Yun Jeong
YJ
Lee
Chung Soo
CS
Bae
Jaeman
J
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D020536:Enzyme Activators / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*
D000972:Antineoplastic Agents, Phytogenic; D020536:Enzyme Activators; D007191:Indazoles; D009363:Neoplasm Proteins; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D006162:Guanylate Cyclase; D002166:Camptothecin