Cross-resistance and collateral sensitivity to natural product drugs in cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cells

Abstract

The cytotoxicity of mitotic spindle poisons, vinca alkaloids and the anthracycline, adriamycin, against cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cell lines was investigated. Interestingly, it was found that all cell lines were more sensitive to the mitotic spindle poisons, vincristine and vinblastine. Adriamycin was the least effective and taxol had intermediate activity. The Walker rat lymphoma cell line resistant to cisplatin (WR) exhibited the multiple drug resistance phenotype since it showed collateral resistance to all drugs (ranging from twofold to taxol, colcemid and colchicine and sixfold to the vinca alkaloids). Verapamil potentiated the cytotoxic activity of adriamycin and vincristine in a striking fashion with the Walker cells. P-glycoprotein was found to be present in the plasma membranes of the Walker cells with approximately a 2.5-fold increase in the WR as compared to the sensitive (WS) cells. Glutathione levels were elevated in all of the cisplatin-resistant cell lines when compared to the cisplatin-sensitive parental cell lines. A profound effect of buthionine sulfoximine pretreatment on adriamycin cytotoxicity was observed. Glutathione S-transferase (pi) was present in all the human cell lines but the WS cells had markedly lower levels (almost negligible) when compared to the WR cells. These observations imply that cisplatin-resistant cells may be more sensitive to mitotic spindle poisons and vinca alkaloids, irrespective of the mechanism of platinum resistance, and that the cytotoxicity of vinca alkaloids could be further modulated by verapamil, irrespective of the presence or absence of P-glycoprotein.

Evaluation of drug transporters' significance for multidrug resistance in head and neck squamous cell carcinoma

“…Cell lines with cisplatin resistance were often sensitive to paclitaxel and vice versa. Such phenomena have already been described for other cancer entities 37–39. However, this obvious inhomogeneity is not clearly reflected by corresponding differences in drug transporter mRNA expression indicating that drug transporters are not the main underlying reason for the observed MDR.…”

Resistance to Paclitaxel in a Cisplatin-Resistant Ovarian Cancer Cell Line Is Mediated by P-Glycoprotein

“…In contrast to other studies [25], short-term cisplatin treatment did not modulate P-gp protein expression, activity or taxane cytotoxicity in IGROVCDDP cells (Figure 1A, 1B, data not shown). It is unusual but not unprecedented to see a model of acquired cisplatin resistance overexpress P-gp (Table 4)[26]–[30]. This most likely represents a generalised stress response to long-term cisplatin treatment as cisplatin is not a P-gp substrate [13].…”

Increased sensitivity to cis-diamminedichloroplatinum induced apoptosis with mitochondrial DNA depletion

“…This suggests that U937 cells, with and without mtDNA, are utilizing glycolysis for the vast majority of ATP synthesis, and that mitochondrial ATP synthesis is not responsible for the current observations No changes were noted in the mRNA expression of MDR1, MRP, BCL2, BAX, ERCC1 or ERCC2 genes in the U937 rho+, rho(7), or cybrid cells. Changes in mRNA expression of these genes in human tumors resistant to cisplatin-induced apoptosis has been noted, with or without cross resistance to other agents (Dabholkar et al, 1992(Dabholkar et al, , 1994Miyashita and Reed, 1993;Lim, 1996;Decaudin et al, 1997;Ara et al, 1994;Biedler, 1994;Chan et al, 1995;Goldstein, 1995;Nooter and Sonneveld, 1993;Rodriguez et al, 1993;Parekh and Simpkins, 1996;Chao, 1995). It has been unclear whether changes in the drug resistance genes MDR1 and MRP and the nucleotide excision repair genes ERCC1 and ERCC2 are mechanistically responsible for changes in cisplatin sensitivity in the studied tissues, or unrelated to the phenotype (Dabholkar et al, 1992(Dabholkar et al, , 1994Biedler, 1994;Chan et al, 1995;Goldstein, 1995;Nooter and Sonneveld, 1993;Rodriguez et al, 1993;Parekh and Simpkins, 1996;Chao, 1995).…”