Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

Abstract

Summary Recent data suggest that expression of the membrane P 170 -glycoprotein (P-gp) may confer resistance to the topoisomerase-I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 µM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function.

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

“…Because SKOV-3TR2 cell line was more resistant to TOP than SKOV-3TR1 cell line this suggested another additional mechanism responsible for TOP-resistance in this cell line. It has been reported that P-gp expression can also be related to TOPresistance (40,41). This observation was confirmed by our previous studies (16,18).…”

Combination Treatment With Trabectedin and Irinotecan or Topotecan Has Synergistic Effects Against Ovarian Clear Cell Carcinoma Cells

“…P-glycoprotein is encoded by the multidrug resistance 1 gene and is known to be involved in multidrug resistance, including resistance to irinotecan 29 and topotecan. 30 As shown in Figure 2B, RMG1-YR, trabectedin-resistant cells, displayed significantly greater P-gp expression than their representative parental cell lines, which strongly indicated that P-gp was involved in their trabectedin resistance. Importantly, when these cell lines were treated with SN-38 or topotecan, their P-gp expression was attenuated in a dose-dependent manner.…”

MDR Gene Expression Analysis of Six Drug-Resistant Ovarian Cancer Cell Lines

“…Additionally, we have observed a similar dose-dependent response pattern to topotecan in the paclitaxel resistant cell line, in spite of its low BCRP expression, which may be due to the high levels of P-gp expression in the W1PR cell line. Published reports have suggested that high levels of P-gp expression play a significant role in topotecan resistance [43]. However, two other cell lines with high expression of P-gp, W1DR and W1VR, demonstrated a sensitivity to topotecan.…”