Cisplatin-resistant prostate cancer model: Differences in antioxidant system, apoptosis and cell cycle

Abstract

Differences in the antioxidant system, apoptotic mechanism and in cell cycle between prostatic cell lines could partially elucidate the development of cisplatin resistance. The aim of this study was to identify the most characteristic parameter for a particular cell line and/or a particular cisplatin treatment using a general regression model and to assess whether it is possible to use measured parameters as markers of cisplatin resistance. This study integrates the results of viability, antioxidant, flow cytometric and quantitative PCR assays in order to characterize the resistance of prostate cancer to cisplatin. Cell growth using metabolic- (MTT) and impedance-based assays, the expression of key cell death signaling proteins (p53, Bax and Bcl-2), cell cycle, activity of antioxidant system-related proteins (superoxide dismutase, glutathione peroxidase, glutathione reductase and metallothionein) and free radical scavenging capacity assays [free radicals (FR), ferric reducing antioxidant power (FRAP), ABTS] were analyzed in the cell lines 22Rv1, PC-3 and PNT1A with respect to rising concentrations (0-150 µM) and different length of cisplatin treatment (12-72 h). The non-functional-p53 PC-3 cell line showed decreased BAX (p<0.05) and, in contrast to PNT1A and 22Rv1, no cisplatin-induced effects on cell cycle. All cell lines showed increasing levels of free radical scavenging activity by ABTS, FRAP and FR assays in a time- and dose-dependent manner (r>0.76 at p<0.001 for ABTS, FRAP and FR at p<0.001). PC-3 showed increased (p<0.05) levels of free radical scavenging activity by ABTS and FR methods. These findings, together with significantly elevated MT, decreased p53 and Bax indicate PC-3 to be cisplatin-resistant. The differences in the antioxidant system and apoptotic mechanisms in PC-3 cells may elucidate the development of cisplatin resistance and indicate that this cell line may be further studied as a model of cytostatic resistance.

Dose Effect of Rhenium (I)-diselenoether as Anticancer Drug in Resistant Breast Tumor-bearing Mice After Repeated Administrations

“…A decrease of the content of antioxidant enzymes in cancer cells reduces the efficacy of chemotherapy with carboplatin/paclitaxel (50). A relationship was observed between the degree of resistance to cytotoxic drug and the oxidative system in a cisplatin-resistant prostate cancer model (51). All these studies show the importance of investigating oxidative stress in patients with cancer.…”

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

“…This resistance is further reflected in the lack of stimulation of the proportion of HaCaT cells in the subG1 fraction by cisplatin (Tables 2 and 3). This is likely due to the mutation in both alleles of p53 in HaCaT cells [104, 105], since it has been shown that cells with p53 mutation or p53 silencing are resistant to cisplatin-induced apoptosis [106, 107]. Cell cycle distribution analysis showed that 24 h pretreatment of HaCaT keratinocytes with 100 nM 1,25(OH) 2 D 3 or calcipotriol resulted in an increase in the proportion of cells in the G2/M phase of the cell cycle following incubation with 120 μM cisplatin for 24 h (Table 3).…”

The timing of caffeic acid treatment with cisplatin determines sensitization or resistance of ovarian carcinoma cell lines

“…as observed in patients with colorectal, lung and prostate cancer) [12], [13], [14] or acquired following cisplatin chemotherapy (as often seen in patients with ovarian cancer) [15]. The mechanisms of cisplatin resistance had been studied in several types of cisplatin resistant cell lines and appear to be multifactorial.…”