Investigation of the Effects of Some Endoplasmic Reticulum Stress-Related Molecules in Combination with Cisplatin on Cisplatin-Resistant Lung Cancer

Project no. 32145 · Status: Kapanmış (Yayın bekleniyor) · 2024

Summary

The development of resistance to cisplatin poses a significant challenge in cancer therapy. This study aimed to investigate the potential synergistic effects of cisplatin in combination with Bortezomib, Eeyarestatin 1, 4µ8c, and GSK2606414 and to explore the reversal of cisplatin resistance in A549 cells resistant to cisplatin (A549/CDDPr).IC50 values for each molecule were determined in A549 and A549/CDDPr cells. Combination treatments at multiples of IC50 doses were applied, and synergistic effects were analyzed using the Combination Index (CI) via CompuSyn software. Western blotting was performed to evaluate the impact of cisplatin and GSK2606414 combinations on ER stress and apoptosis-related proteins, including Perk, BIP, p-Perk, Chop, Parp, and cleaved-Parp.In A549/CDDPr cells, low-dose combinations failed to exhibit synergistic effects. Synergistic effects (CI<1) were observed only in A549 cells with the cisplatin and GSK2606414 combination at specific concentrations. Western blot analysis revealed that, compared to cisplatin alone, combinations containing cisplatin at 10 µM resulted in increased expression of Perk, BIP, and cleaved-Parp, while p-Perk and Chop expression decreased. The combination of 20 µM cisplatin+12,5 µM GSK2606414 suppressed the ER stress response with a significant decrease in PERK, p-PERK, and CHOP levels followed by an increase in BAK, indicating that mitochondria-mediated apoptosis persists and non-UPR apoptotic mechanisms are also involved. The effect of PERK inhibition on the apoptotic response changed with the rise in GSK2606414 dose, and this response was attenuated especially at 25 µM dose, suggesting that high levels of PERK suppression may limit apoptosis and trigger alternative cellular responses.While combinations lacked synergy in A549/CDDPr cells, the observed synergy between cisplatin and GSK2606414 in A549 cells suggests a promising approach for enhancing cisplatin efficacy in non-resistant cancer cells.

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