Cross-talk between signalling pathways and the multidrug resistant proteinMDR-1

The multidrug resistant protein MDR-1 has been associated with the resistan ce to a wide range of anti-cancer drugs. Taxol is a substrate for this tran sporter system and is used in the treatment of a wide range of human malign ancies including lung, breast and ovarian cancer. We have generated a serie s of ovarian cell lines resistant to this compound, all of which overexpres s MDR-1 through gene amplification. We present novel evidence that a consti tutive activation of the ERK1/2 MAP kinase pathway was also observed althou gh the level of active JNK and p38 remained unchanged. Inhibition of the ER K1/2 MAP kinase pathway using UO126 or PD098059 re-sensitised the Taxol res istant cells at least 20-fold. Importantly, when Mdr-1 cDNA was stably expr essed in the wild-type cell line to generate a highly Taxol-resistant sub-l ine, 1847/MDR5, ERK1/2 MAP kinases again became activated. This result demo nstrated that the increased activity of the signalling pathway in the Taxol -resistant lines was directly attributable to MDR-1 overexpression and was not due to the effects of Taxol itself. Additionally, we demonstrated that inhibition of the P13K pathway with LY294002 sensitised the MDR-1-expressin g 1847/TX0.5 cells and 1847/MDR5 cells at least 10-fold but had no effect i n the wild-type cells. This finding suggests a possible role for this pathw ay, also, in the generation of resistance to Taxol. (C) 2001 Cancer Researc h Campaign.