2. Academic Validation
  3. Combination of Vismodegib and Paclitaxel Enhances Cytotoxicity via Bak-mediated Mitochondrial Damage in EGFR-Mutant Non-Small Cell Lung Cancer Cells

Combination of Vismodegib and Paclitaxel Enhances Cytotoxicity via Bak-mediated Mitochondrial Damage in EGFR-Mutant Non-Small Cell Lung Cancer Cells

  • Cell Biochem Biophys. 2024 Jul 19. doi: 10.1007/s12013-024-01438-y.
Wei-Chen Yeh 1,  Yun-Chieh Tu 1,  Pei-Ling Hsu 2 3,  Chu-Wan Lee 4,  Hsin-Hsien Yu 5 6,  Bor-Chyuan Su 7 8
Affiliations

Affiliations

  • 1 School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
  • 3 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan.
  • 4 Department of Nursing, National Tainan Junior College of Nursing, 78, Section 2, Minzu Road, West Central District, Tainan, 70007, Taiwan.
  • 5 Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. yuhsinhsien@tmu.edu.tw.
  • 6 Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. yuhsinhsien@tmu.edu.tw.
  • 7 Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. subc8265@tmu.edu.tw.
  • 8 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. subc8265@tmu.edu.tw.
PMID: 39030332 DOI: 10.1007/s12013-024-01438-y
Abstract

Half of NSCLC patients harbor epidermal growth factor receptor (EGFR) mutations, and their therapeutic responses are remarkably different from patients with wild-type EGFR (EGFR-WT) NSCLC. We previously demonstrated that the Hedgehog Inhibitor vismodegib (Vis) potentiates paclitaxel (PTX)-induced cytotoxicity via suppression of Bax phosphorylation, which promotes accumulation of mitochondrial damage and Apoptosis in EGFR-WT NSCLC cells. In this study, we further delineated the Anticancer activity and underlying mechanisms of this combination treatment in EGFR-mutant NSCLC cells. MTS/PMS activity and trypan blue exclusion assays were used to assess cell viability. Apoptosis was monitored by chromosome condensation, annexin V staining, and cleavage of PARP and Caspase-3. Western blots were conducted to track proteins of interest after treatment. Reactive Oxygen Species (ROS) level was monitored by 2',7'-dichlorodihydrofluorescein diacetate. Mitochondrial status was analyzed by tetramethylrhodamine, ethyl ester. Hedgehog signaling was induced by PTX, which rendered H1975 and PC9 cells insensitive to PTX-induced mitochondrial Apoptosis via suppression of Bak. However, Vis enhanced PTX-induced Bak activation, leading to mitochondrial damage, ROS accumulation, and subsequent Apoptosis. Our findings suggest that the combination of Vis and PTX could be a potential therapeutic strategy to increase PTX sensitivity of EGFR-mutant NSCLC.

Keywords

Bak; EGFR mutation; Hedgehog; Lung cancer; Paclitaxel.

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