1. Synergistic effects of MK-1775 and gemcitabine on cytotoxicity in non-small cell lung cancer.
- Author
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Chen CP, Hung TH, Hsu PC, Yeh CN, Huang WK, Pan YR, Hsiao YT, Lo CH, and Wu CE
- Abstract
Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Chemotherapy is crucial in NSCLC treatment, and targeting Wee1 kinase, a key regulator of the G2/M cell cycle checkpoint, may enhance the efficacy of cytotoxic agents. This study investigates the potential of the Wee1 inhibitor MK-1775 in combination with gemcitabine and pemetrexed to enhance cytotoxicity in NSCLC cell lines., Methods: Human NSCLC cell lines H1975, HCC827, A549, and H460 were treated with MK-1775 and chemotherapeutic agents, both alone and in combination. Growth inhibitory effects were assessed using the CCK8 assay. Apoptotic markers were evaluated via Western blotting, and cell cycle distribution was analyzed using FACS. In vivo efficacy was assessed using xenograft mouse models with H1975 and H460 cells, monitoring tumor growth and treatment toxicity., Results: MK-1775 combined with gemcitabine or pemetrexed significantly decreased cell survival rates and IC
50 values in A549 and HCC827 cell lines. Increased levels of phosphorylated cdc2, γ-H2AX, and PARP indicated enhanced apoptosis. Cell cycle analysis revealed G2/M phase arrest in p53-mutant HCC827 and H1975 cells treated with MK-1775 and gemcitabine. In xenograft models, the combination significantly inhibited tumor growth without significant toxicity., Conclusions: MK-1775 enhances the cytotoxic effects of gemcitabine and pemetrexed in NSCLC cell lines and effectively inhibits tumor growth in vivo . These findings suggest that Wee1 inhibition by MK-1775, combined with chemotherapy, represents a promising therapeutic strategy for NSCLC treatment., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chiao-En Wu reports financial support was provided by 10.13039/100020595National Science and Technology Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)- Published
- 2024
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