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
4614 - Predictors of Response to Checkpoint Inhibitors in Naïve and Ipilimumab-Refractory Melanoma
Presenter: Domenico Mallardo
Session: Poster Display session 3
Resources:
Abstract
2901 - IFN-γ/IL-10 ratio as predictive biomarker for response to anti-PD-1 therapy in metastatic melanoma patients
Presenter: Emilio Giunta
Session: Poster Display session 3
Resources:
Abstract
2306 - Multiplex Chromogenic Immunohistochemistry (IHC) for Spatial Analysis of Checkpoint-Positive Tumor Infiltrating Lymphocytes (TILs)
Presenter: Scott Ely
Session: Poster Display session 3
Resources:
Abstract
1678 - The role of PD-L1 expression as a predictive biomarker in advanced renal cell carcinoma: a meta-analysis of randomized clinical trials.
Presenter: Alberto Carretero-Gonzalez
Session: Poster Display session 3
Resources:
Abstract
5138 - Radiomic Features as a Non-invasive Biomarker to Predict Response to Immunotherapy in Recurrent or Metastatic Urothelial Carcinoma
Presenter: Kye Jin Park
Session: Poster Display session 3
Resources:
Abstract
5800 - Integrative combination of high-plex digital profiling techniques and cluster analysis to reveal complex immune biology in the tumor microenvironment of mesothelioma
Presenter: Carmen Ballesteros-Merino
Session: Poster Display session 3
Resources:
Abstract
5736 - Predictive factors of response to immunotherapy in 198 patients with metastatic non-microcytic lung cancer (mNSCLC): real world data from 2 university hospitals in Spain
Presenter: Juan Felipe Cordoba Ortega
Session: Poster Display session 3
Resources:
Abstract
5645 - Evaluating Lung CT Density Changes Among Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) Treated with Thoracic Radiotherapy (TRT) alone or TRT Followed by Combined Ipilimumab (IPI) and Nivolumab (NIVO).
Presenter: Kujtim Latifi
Session: Poster Display session 3
Resources:
Abstract
1540 - Immuno-oncology therapy biomarkers differences between polyoma-virus positive and negative Merkel cell carcinomas
Presenter: Zoran Gatalica
Session: Poster Display session 3
Resources:
Abstract
4538 - Can we improve patient selection for phase 1 clinical trials (Ph1) based on Immuno-Oncology score prognostic index (VIO)?
Presenter: Ignacio Matos Garcia
Session: Poster Display session 3
Resources:
Abstract