Analysis of MDR genes expression and cross-resistance in eight drug resistant ovarian cancer cell lines

Abstract

BackgroundMultiple drug resistance (MDR) of cancer cells is the main reason of intrinsic or acquired insensitivity to chemotherapy in many cancers. In this study we used ovarian cancer model of acquired drug resistance to study development of MDR.We have developed eight drug resistant cell lines from A2780 ovarian cancer cell line: two cell lines resistant to each drug commonly used in ovarian cancer chemotherapy: cisplatin (CIS), paclitaxel (PAC), doxorubicin (DOX) and topotecan (TOP). A chemosensitivity assay - MTT was performed to assess drug cross-resistance. Quantitative real-time polymerase chain reaction and immunofluorescence were also performed to determine mRNA and protein expression of genes/proteins involved in drug resistance (P-gp, BCRP, MRP1, MRP2, MVP). Flow cytometry was used to determine the activity of drug transporters.ResultsWe could observe cross-resistance between PAC- and DOX-resistant cell lines. Additionally, both PAC-resistant cell lines were cross-resistant to TOP and both TOP-resistant cell lines were cross-resistant to DOX. We observed two different mechanisms of resistance to TOP related to P-gp and BCRP expression and activity. P-gp and BCRP were also involved in DOX resistance. Expression of MRP2 was increased in CIS-resistant cell lines and increased MVP expression was observed in CIS-, PAC- and TOP-, but not in DOX-resistant cell lines.ConclusionsEffectiveness of TOP and DOX in second line of chemotherapy in ovarian cancer can be limited because of their cross-resistance to PAC. Moreover, cross-resistance of PAC-resistant cell line to CIS suggests that such interaction between those drugs might also be probable in clinic.

New and Old Genes Associated with Topotecan Resistance Development in Ovarian Cancer Cell Lines

“…Expression of this gene was reported among others in breast and ovarian cancer and cancer cell lines (13)(14)(15)(16)(17). In our previous study we observed that TOP resistance could be also related to expression of glycoprotein P (P-gp) encoded by ABCB1 (MDR1) gene (16,18). Recently we reported the up-regulation of many collagen genes in TOPresistant ovarian cancer cell lines (19,20).…”

“…The main protein responsible for active removal of TOP from cancer cells is BCRP (breast cancer resistant protein) encoded by ABCG2 gene. Expression of this gene was reported among others in breast and ovarian cancer and cancer cell lines (13)(14)(15)(16)(17). In our previous study we observed that TOP resistance could be also related to expression of glycoprotein P (P-gp) encoded by ABCB1 (MDR1) gene (16,18).…”

“…SKOV-3TR2 cell line was nearly four times more resistant than SKOV-3TR1 cell line. The TOP sensitivity of A2780 and W1 resistant sublines were determined previously (16,18). TOP-resistant variants of A2780 and W1 cell lines (16,18).…”

Effects of major parameters of nanoparticles on their physical and chemical properties and recent application of nanodrug delivery system in targeted chemotherapy

“…[15][16][17][18][19][20] There has been much research on the mechanism of MDR in the recent years, 21,22 and scientists are trying to explore the mechanisms to overcome MDR such that chemotherapy drugs could exhibit a higher efficacy.…”

In�vitro study on reversal of ovarian cancer cell resistance to cisplatin by naringin via the nuclear factor-κB signaling pathway

“…P-gp discharges multiple cytoxic drugs using ATP within the cells, which increases the resistance of tumor cells to pharmacological agents, thereby causing the resistance of tumor cells (24). MDR1/P-gp is expressed in almost all human tumor cells to different degrees, and its expression in tumors insensitive to chemotherapy or with poor efficacy is often high (25). Previous studies have reported that the sensitivity of some cancer patients to chemotherapy was increased following the administration of P-gp inhibitors (24,(26)(27)(28).…”