Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells.

Background: Bcl-2 plays a major role in the pathobiology and drug resistance of ovarian cancer, and inhibition of bcl-2 was useful for OC therapy. It has previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in many cancer cells. In the present study,we investigate the effect of TW-37 or / and in combination with cisplain on several ovarian cancer (OC) cell lines with high bcl-2 expression.

Methods: The bcl-2 mRNA and protein expression, and the cisplain (DDP) sensitivity of OC cell lines SKOV3, OVCAR3, OV-90 and 3AO and SKOV3DDP were determined by Quantitative real-time RT-PCR,Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting (MTT) assays. The effects of TW-37 alone or combined with cisplain on growth and apoptosis in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells was detected by MTT,clonogenic assay, ELISA and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay.

Results: The cell lines SKOV3 and 3AO were sensitive, whereas OVCAR3, OV-90 and SKOV3DDP were resistant to cisplain. Significant positive correlation was observed between basal bcl-2 mRNA and protein and cisplain sensitivity. Cisplain treatment did not activate bcl-2 in vitro. Treatment with TW-37 inhibited bcl-2 expression in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells , and inhibited growth and induced apoptosis ,and increased cisplain killing of the bcl-2 overexpressed cells in a does and time-dependant manner in vitro.

Conclusion: Bcl-2 level positively correlated with sensitivity to cisplain. Treatment with TW-37 was effective alone and in combination with cisplain in bcl-2 overexpressed OC cell lines in vitro. Thus, TW-37 may be a useful therapeutic agent for OCs.