Induction of resistance to Aplidin® in a human ovarian cancer cell line related to MDR expression

Abstract

Aplidin® resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin® for 8 months, starting from a concentration of 10 nM to a final concentration of 4 µM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin®. IGROV-1/APL resistant cell line shows the typical MDR phenotype: (i) increased expression of membrane-associated P-glycoprotein, (ii) cross-resistance to drugs like etoposide, doxorubicin, vinblastine, vincristine, taxol, colchicin and the novel anticancer drug Yondelis™ (ET-743). The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin® by increasing the drug intracellular concentration. The resistance to Aplidin® was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells overexpressing Pgp are resistant to Aplidin® was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin® compared to the CEM parental cell line.