Synergistic effects of MK-1775 and gemcitabine on cytotoxicity in non-small cell lung cancer
Chiao-Ping Chen,
Tsai-Hsien Hung,
Ping-Chih Hsu,
Chun-Nan Yeh,
Wen-Kuan Huang,
Yi-Ru Pan,
Yu-Tien Hsiao,
Chih-Hong Lo,
Chiao-En Wu
Affiliations
Chiao-Ping Chen
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Tsai-Hsien Hung
Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Ping-Chih Hsu
Division of Thoracic Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Chun-Nan Yeh
Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of General Surgery, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Wen-Kuan Huang
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Yi-Ru Pan
Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of General Surgery, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan
Yu-Tien Hsiao
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Chih-Hong Lo
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
Chiao-En Wu
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital (Built and Operated by Chang Gung Medical Foundation), New Taipei City, Taiwan; Corresponding author. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan.
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 IC50 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.
