Multidrug resistance in androgen-independent growing rat prostate carcinoma cells is mediated by P-glycoprotein

Abstract

Prostate carcinomas are in general resistant against virtually all cytotoxic drugs. Up to now it has not been thoroughly evaluated whether specific resistance factors, such as the expression of the MDR1 gene, play a role in this multi-agent resistance and whether there is a link between drug resistance and hormone-independent growth. We investigated the resistance patterns of a hormone-sensitive and four hormone-independent Dunning rat carcinoma sublines against four drugs which are substrates of P-glycoprotein (vinblastine, taxol, doxorubicin, and etoposide) and two agents (methotrexate and cis-platinum) which are not transported by this efflux pump. All hormone-insensitive sublines, AT.1, AT. 3.1., MatLu and Mat LyLu, continuously showed a clearly enhanced resistance (3- to 26-fold) against the P-glycoprotein substrates, compared to the hormone-sensitive subline G. Only two of the androgen-independent sublines displayed enhanced resistance against methotrexate, whereas all of them were more sensitive against cisplatin than the androgen-sensitive G cells. By addition of verapamil the resistance against vinblastine (9- to 10-fold) and taxol (6.7- to 26.7-fold) in the hormone-insensitive cells could be almost totally reversed. Furthermore, the fluorescent P-glycoprotein substrate rhodamine-123 was effectively pumped out of the four tested hormone-independent cell lines, whereas the hormone-sensitive G cells were unable to extrude the dye. By reverse transcriptase polymerase chain reaction (RT-PCR) with primers specific for the rat mdr1b gene, the homologue to the human MDR1 gene, we could easily detect mdr1b expression in the androgen independent cell lines, but not in the G cells. Our results suggest that the product of the rat mdr1b gene is involved in the multidrug resistance of androgen-independent Dunning prostate carcinoma cells.

Diagnostic and Prognostic Information in Prostate Cancer with the Help of a Small Set of Hypermethylated Gene Loci

“…In the case of GSTP1 and APC, we expected and found a high rate of gene silencing by epigenetic hypermethylation in prostate cancer and practically no methylation in BPH or control tissue. In contrast, we initially expected the MDR1 gene loci to be activated and therefore hypomethylated in prostate cancer because its expression correlates with resistance to hormone sensitivity and is thought to be important in the progression of primarily hormone/androgen-sensitive malignancies like prostate cancer (31,34,35). Surprisingly, we found that the MDR1 locus is hypermethylated in prostate cancer and BPH.…”

Priming cancer cells for drug resistance: role of the fibroblast niche

“…However, ABC proteins are actively exploited by cancer cells. One member of the ABC family, ABCC1 (P-Glycoprotein) is known to promote drug resistance to doxorubicin in breast, prostate and lung cancer cells (Keizer et al, 1989; Binaschi et al, 1995; Siegsmund et al, 1997; Wartenberg et al, 1998). ABCC1 has also been implicated in resistance to 5-FU in lung and liver cancer (Jin et al, 2002; Dačević et al, 2013), and alkylating agents, such as Vinblastine, in breast, lung and ovarian cancer cells (Adams and Knick, 1995).…”

Multidrug Resistance in Prostate Cancer

“…Rat mdr1b mRNA was found in hormone-insensitive sublines of Dunning rat prostate carcinoma cells. Reversal of resistance against vinblastine and paclitaxel was achieved with verapamil [23]. Ketoconazole has been described as MDR reversing agent in prostate cancer [7].…”