Induction of apoptosis by the new anticancer drug XK469 in human ovarian cancer cell lines.
XK469, a synthetic quinoxaline phenoxypropionic acid derivative, has been found to have selective activity against a broad panel of solid tumors including several drug-resistant cell lines and has been approved for phase I clinical evaluation. Recent studies suggested that XK469 is a selective topoisomerase IIbeta inhibitor, but the mechanism of XK469-induced cell death remains unknown. Here we investigate the ability of XK469 to induce apoptosis of human cancer cells. In the human ovarian cancer cell line PA1, XK469 caused the release of cytochrome c, activation of caspases including caspases 9, 7 and 3, cleavage of PARP, and subsequently cell death. Moreover, Bcl2 and Bax were cleaved in XK469 treated cells. PA1 cells expressing the dominant negative-caspase 9 were less sensitive to XK469. Importantly, in these PA1 cells expressing DN-casp 9, the activation of caspases including caspases 3, 7 and 9, and cleavage of Bax and Bcl2 were inhibited, suggesting that the activation of the mitochondrial pathway is required for XK469-induced anticancer activity. These results indicate that the induction of apoptosis by XK469 may account for its anti-tumor activity and such activity is required for the activation of the mitochondrial pathway. Thus, our study defines a possible mechanism, at least in part, underlying XK469-induced anti-cancer activity.
Ding
Zhenhua
Z
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit 48201, USA.
Zhou
Jun-Ying
JY
Wei
Wei-Zen
WZ
Baker
Vicki V
VV
Wu
Gen Sheng
GS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; C118180:XK 469; D051028:bcl-2-Associated X Protein; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases