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Targeting the PERK/NRF2 pathway: Enhancing cisplatin efficacy in resistant ovarian cancer cells via MRP1 and ROS
Seyedeh Sara Ghorbanhosseini1, Mitra Nourbakhsh2, Fatemeh Mosaffa3
1Department of Clinical Biochemistry, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran.
Abstract:
Overcoming chemotherapy resistance remains a pivotal challenge in ovarian cancer treatment. This study investigates the potential of combining cisplatin with GSK2606414, a PERK inhibitor, to enhance therapeutic efficacy against cisplatin-resistant ovarian cancer cells. cisplatin resistance is driven by the PERK/NRF2 pathway, which activates MRP1 upregulation and antioxidant defenses, thus promoting cell survival. By inhibiting PERK phosphorylation, GSK2606414 disrupts this pathway, downregulating MRP1 and increasing oxidative stress to sensitize cancer cells to cisplatin. Our findings reveal that the GSK2606414-cisplatin combination significantly reduces cell viability and proliferation, particularly in resistant cell lines, allowing for dose reduction and potentially lower side effects. The combined therapy also amplifies, increasing Caspase-12 and CHOP protein levels during endoplasmic reticulum stress. By targeting the p-PERK/p-NRF2/MRP1 and p-PERK/p-NRF2/SOD pathways, GSK2606414 decreases MRP1 expression and elevates ROS levels, rendering resistant cells more susceptible to chemotherapy. Additionally, this combination boosts intracellular cisplatin accumulation in both cisplatin-sensitive and -resistant ovarian cancer cell lines, reinforcing its cytotoxic impact. These findings underscore the promise of GSK2606414 and cisplatin co-treatment as a potent strategy to counteract ovarian cancer resistance. This combination could potentially advance therapeutic outcomes and provide a new pharmacological approach to resistant cancers.
Insights
Combining cisplatin with PERK inhibitor GSK2606414 overcomes chemotherapy resistance in ovarian cancer. This strategy downregulates survival pathways, increasing cancer cell sensitivity to cisplatin and reducing viability.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy resistance is a major obstacle in ovarian cancer treatment.
- The PERK/NRF2 pathway, involving MRP1 upregulation and antioxidant defenses, promotes survival in cisplatin-resistant ovarian cancer cells.
Purpose of the Study:
- To investigate the efficacy of combining cisplatin with GSK2606414, a PERK inhibitor, against cisplatin-resistant ovarian cancer.
- To elucidate the molecular mechanisms underlying the combined therapy's effect on chemoresistance.
Main Methods:
- Utilized GSK2606414 to inhibit PERK phosphorylation in cisplatin-resistant ovarian cancer cells.
- Assessed cell viability, proliferation, apoptosis markers (Caspase-12, CHOP), MRP1 expression, ROS levels, and intracellular cisplatin accumulation.
Main Results:
- The combination of GSK2606414 and cisplatin significantly reduced cell viability and proliferation in resistant ovarian cancer cells.
- Inhibition of PERK phosphorylation downregulated MRP1 and SOD, elevated ROS levels, and increased endoplasmic reticulum stress markers.
- The combined therapy enhanced intracellular cisplatin accumulation and sensitized resistant cells to chemotherapy.
Conclusions:
- The combination of GSK2606414 and cisplatin is a promising strategy to overcome ovarian cancer chemotherapy resistance.
- Targeting the PERK/NRF2 pathway with GSK2606414 resensitizes resistant ovarian cancer cells to cisplatin, potentially improving therapeutic outcomes.
