Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: therapeutic potential for ovarian cancer.
Drug resistance is a major concern in the successful treatment of ovarian cancer. In the present study we report a combinational drug regime using arsenic trioxide (ATO) and cisplatin (CDDP) to increase therapeutic potentiality in ovarian cancer cells. ATO-mediated growth inhibition and apoptosis in human suspension ovarian cancer COC1 cells were evaluated by MTT assay and annexin V assay using flow cytometry, respectively. cDNA arrays were performed to screen ATO-mediated gene expression. Treatment of COC1 cells with ATO alone resulted in growth inhibition and apoptosis with a dose-and time-dependent fashion; further cDNA arrays showed that 34 genes (23 up-regulated genes and 11 down-regulated genes) may strongly associate with the antiproliferative and pro-apoptotic effects induced by ATO. Furthermore, Chou-Talalay analysis was used to evaluate the combinational effect of ATO and CDDP as well as dose-reduction index (DRI) in a panel of ovarian cancer cells including CDDP-sensitive and -resistant cell lines. The combination index (CI) analysis indicated that the interaction effect of ATO/CDDP exhibited a wide range of synergism in all the adherent ovarian cancer cells (A2780, IGROV-1, SKOV-3, and R182) as well as 0.93 to 0.69 for IC(50) to IC(90) in suspension COC1 cells where CI < 1, =1, and >1, define synergism, additive effect, and antagonism, respectively. More intriguingly, the combination of ATO and CDDP yielded favorable DRIs ranging from 1.23-fold to 13.51-fold dose reduction. These results suggest that ATO and its combination with CDDP present therapeutic potential for ovarian cancer, and deserve further preclinical and clinical studies.
Zhang
Ning
N
Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Wu
Zhen-Ming
ZM
McGowan
Eileen
E
Shi
Jun
J
Hong
Zu-Bei
ZB
Ding
Chuan-Wei
CW
Xia
Pu
P
Di
Wen
W
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D002945:Cisplatin; D000077237:Arsenic Trioxide