3842 - Effect of docetaxel-resistance on the reactivity of prostate cancer cells to metformin

Background

Metronomic approach represent a promising strategy for the chemotherapy of drug-resistant tumors, because it can reduce the effective doses and adverse effects of chemotherapeutics. In particular, metabolic blockers reduce energy supply for multi-drug resistance systems, thus increasing tumor cells’ reactivity to chemotherapeutics. Metformin is an anti-diabetic drug that blocks mitochondrial respiration, interferes with ATP production and with proliferation of cancer cells. However, the effect of drug-resistance of prostate cancer cells on their reactivity to metformin has not yet been evaluated.

Methods

Here, we analysed short- and long-term cytotoxic and pro-apoptotic effects of metformin on the phenotype of human prostate cancer PC-3 and DU145 cells and their docetaxel (DCX)-resistant lineages (PC-3-DCX20 and DU145_DCX20; obtained after long-term treatment with 20 nM DCX). We concentrated on their DCX-resistance pattern and compared their epithelial-mesenchymal transition (EMT)-related phenotype, invasive potential and the activity of ATP-binding cassette (ABC) transporters in the presence of metformin and/or DCX.

Results

Metformin increased the sensitivity of drug-resistant PC-3 and DU145 cells to DCX; even though PC-3_DCX20 cells displayed reduced sensitivity to combined metformin/DCX treatment. When administered alone, metformin exerted less prominent cytostatic effects on PC_DCX20 cells than on their DU145_DCX20 counterparts. This effect was accompanied by EMT-related morphological changes, accompanied by the up-regulation of connexin (Cx)43.

Conclusions

These data indicate that reactivity of drug-resistant prostate cancer cells to metformin may depend on the efficiency of metabolic stress-induced EMT. EMT-related metabolic elasticity that apparently increases invasive potential of PC3 cells in the absence of DCX may limit the application of metformin in therapy of drug-resistant prostate tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Jagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.