Paclitaxel and SN-38 overcome cisplatin resistance of ovarian cancer cell lines by down-regulating the influx and efflux system of cisplatin

Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an act ive metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs ma ove rcome the intrinsic and/or acquired resistance of cancer cells to DDR we in vestigated the effect of a combination of DDP with paclitaxel and a combina tion of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsica lly resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations sho wed additive to synergistic antitumor activity. A time-dependent platinum ( Pt) accumulation was observed in the DDP-sensitive KF cell line, while a de crease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines b y exposure to paclitaxel or SN-38. Ouabain. a Na+,K+-ATPase inhibitor, decr eased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxe l- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP). which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DD P alone. These results suggest that paclitaxel and SN-38 overcome DDP resis tance of ovarian cell lines by controlling intracellular accumulation of DD P via both the influx and efflux systems.