Diverse cross-resistance phenotype to Yondelis (Trabectedin; ET-743) and Zalypsis (PM00104) in paclitaxel, doxorubicin and cisplatin selected multidrug resistant cell lines Free

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Yondelis® (trabectedin, ET-743) and Zalypsis (PM00104) are marine derived compounds that have antitumor activity. The former has shown significant antitumor activity in sarcomas as well as in advanced breast and ovarian cancer. Recent studies suggest a complex relationship between ABCB1/MDR1 (Pgp1) expression and Yondelis resistance in tumor cells. The present study was performed to further investigate the relationship between expression of ABCB1 or, ABCC1/MRP1 with resistance to Yondelis or Zalypsis. First, we analyzed several multidrug resistant cell lines include human osteosarcoma (U-2OS_TR), ovarian (SKOV-3_TR, OVCAR8_TR), breast (MCF-7_TR) and colon (SW480_TR) cancer cell lines that were initially induced to be resistant to paclitaxel. We observed that these cell lines expressed high levels of ABCB1 (but not ABCC1 or ABCG2/BCRP) and did not demonstrate cross-resistance to either Yondelis or Zalypsis. In contrast, the multidrug resistant cell lines (human osteosarcoma (U-2OS_R2 and KHOS_R2), uterine sarcoma (MES-SA/Dx5), and breast cancer (MCF-7_DR) cell lines that were originally induced to be resistant to doxorubicin also expressed high level of ABCB1 (but not ABCC1 or ABCG2) but did demonstrate significant resistance to both Yondelis and Zalypsis. The above paclitaxel resistant cell lines demonstrated cross-resistance to doxorubicin, vincristine and mitoxantrane, while most of the above doxorubicin resistant cell lines demonstrated cross-resistantce to paclitaxel and, vincristine but not to mitoxantrane. Cisplatin and gemcitabine drug resistant cell lines (IGROV1cp,2008cp70 and OVCAR5_GR) demonstrated no cross-resistance to paclitaxel, doxorubicin, Yondelis or Zalypsis. siRNA down-regulating ABCB1 expression in doxorubicin resistant cell lines caused partial sensitization of these cells to both doxorubicin and paclitaxel but not to either Yondelis or Zalypsis. These results indicate that cell lines initially induced to be resistant to either paclitaxel or doxorubicin (are cross resistant to many other drugs) and ABCB1 overexpression alone is not sufficient to confer resistance to either Yondelis or Zalypsis. Such diverse cross-resistance phenotype observed in these multidrug resistant cell lines seems to be associated with the initial exposure drug but not to ABCB1 expression. This study demonstrates that a common molecular pathway other than ABCB1 may be involved in the resistance to Yondelis or Zalypsis.