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Published on: February 7, 2018
Collateral sensitivity: ABCG2-overexpressing cells are more vulnerable to oxidative stress
Damian Krzyżanowski1, Grzegorz Bartosz1, Agnieszka Grzelak1
1Department of Molecular Biophysics, University of Łódź, Łódź 90-237, Poland.
Abstract:
Multidrug resistance (MDR), which is the main obstacle to cancer chemotherapy, is mainly due to overexpression of ATP-binding cassette (ABC) transporters, especially ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP). A novel idea to overcome MDR is that of collateral sensitivity, i.e., finding a treatment to which cells overexpressing ABC transporters are more sensitive than cells that do not overexpress them. In this study we demonstrate for the first time that MDCKII-BCRP cells, overexpressing ABCG2, are more vulnerable to exogenous oxidative stress induced by several oxidants, viz. paraquat, menadione, hydrogen peroxide, tert-butylperoxide, and 2,2-azobis(2-methylpropionamidine) dihydrochloride. MDCKII-BCRP cells have significantly decreased glutathione level and decreased activities of glutathione S-transferase and glutathione reductase, which may underlie their augmented vulnerability to oxidative stress. These results suggest the possibility of using agents that induce oxidative stress to selectively kill cells overexpressing BCRP.
Insights
Cancer cells overexpressing the BCRP transporter show increased sensitivity to oxidative stress. This finding suggests using oxidants to selectively target BCRP-overexpressing cancer cells, potentially overcoming multidrug resistance.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) in cancer chemotherapy is primarily caused by ATP-binding cassette (ABC) transporters, notably ABCB1, ABCC1, and ABCG2.
- Collateral sensitivity, where cancer cells overexpressing ABC transporters are more sensitive to specific treatments, offers a novel strategy to overcome MDR.
Purpose of the Study:
- To investigate the sensitivity of cells overexpressing ABCG2 (BCRP) to exogenous oxidative stress.
- To explore the potential of oxidative stress-inducing agents as a targeted therapy against BCRP-overexpressing cancer cells.
Main Methods:
- Utilized MDCKII-BCRP cells, which overexpress ABCG2.
- Exposed cells to various oxidants, including paraquat, menadione, hydrogen peroxide, tert-butylperoxide, and 2,2-azobis(2-methylpropionamidine) dihydrochloride.
- Assessed cellular glutathione levels and the activities of glutathione S-transferase and glutathione reductase.
Main Results:
- MDCKII-BCRP cells demonstrated heightened vulnerability to exogenous oxidative stress induced by multiple oxidants.
- Significantly decreased glutathione levels and reduced activities of glutathione S-transferase and glutathione reductase were observed in MDCKII-BCRP cells.
- These biochemical alterations may explain the increased sensitivity to oxidative stress.
Conclusions:
- Cells overexpressing ABCG2 (BCRP) are more susceptible to oxidative stress.
- Agents that induce oxidative stress could be a promising therapeutic approach for selectively eliminating BCRP-overexpressing cancer cells.
- This strategy holds potential for overcoming BCRP-mediated multidrug resistance in cancer therapy.
