Abstract 3842
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.
Resources from the same session
3264 - A novel preclinical model of RAF-independent MEK1 mutant tumors and its treatment with novel ATP competitive MEK inhibitor
Presenter: Luca Hegedus
Session: Poster Display session 3
Resources:
Abstract
4918 - HER2 inhibition in Aggressive Squamous Cell Carcinomas driven by a common MET Sema Domain Polymorphism
Presenter: Nur Afiqah Mohamed Salleh
Session: Poster Display session 3
Resources:
Abstract
2426 - ADAM9 as a target for lung cancer treatment
Presenter: Yuh-pyng Sher
Session: Poster Display session 3
Resources:
Abstract
5537 - Novel polyurea/polyurethane nanocapsules loaded with a tambjamine analog to improve cancer chemotherapy delivery and safety in lung cancer
Presenter: Marta Perez Hernandez
Session: Poster Display session 3
Resources:
Abstract
1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer
Presenter: Hsing-pang Hsieh
Session: Poster Display session 3
Resources:
Abstract
3543 - Molecular characteristics in lung squamous cell carcinomas dependent on TP53 status – putative targets
Presenter: Vilde Haakensen
Session: Poster Display session 3
Resources:
Abstract
4111 - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer
Presenter: Asuka Kawachi
Session: Poster Display session 3
Resources:
Abstract
4559 - Treatment with BLU-667, a potent and selective RET inhibitor, provides rapid clearance of ctDNA in Patients with RET-altered Non-Small Cell Lung Cancer (NSCLC) and Thyroid Cancer
Presenter: Giuseppe Curigliano
Session: Poster Display session 3
Resources:
Abstract
2501 - Triple MET/SRC/PIM inhibition in MET addicted tumors
Presenter: Ilaria Attili
Session: Poster Display session 3
Resources:
Abstract
5655 - Bioactivation of napabucasin triggers reactive oxygen species–mediated cancer cell death
Presenter: Fieke Froeling
Session: Poster Display session 3
Resources:
Abstract