Verteporfin Exerts Anticancer Effects and Reverses Resistance to Paclitaxel via Inducing Ferroptosis in Esophageal Squamous Cell Cancer Cells

• Published in: Molecular biotechnology 2024-09, Vol.66 (9), p.2558-2568
• Main Authors: Wang, Xue-Wei, Yang, Zi-Yi, Li, Ting, Zhao, Xin-Ran, Li, Xiao-Zhong, Wang, Xiao-Xia
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Biochemistry; Biological Techniques; Biotechnology; Cell Biology; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Cell viability; Chemistry; Chemistry and Materials Science; Cyclohexylamines; Drug Resistance, Neoplasm - drug effects; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Ferroptosis; Ferroptosis - drug effects; Glutathione; Glutathione peroxidase; Human Genetics; Humans; Inhibitors; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mortality; Original Paper; Paclitaxel; Paclitaxel - pharmacology; Peroxidase; Phenylenediamines - pharmacology; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Protein Science; Reactive oxygen species; Reactive Oxygen Species - metabolism; Squamous cell carcinoma; Verteporfin - pharmacology; Yes-associated protein
• ISSN: 1073-6085; 1559-0305; 1559-0305
• DOI: 10.1007/s12033-023-00891-z

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Ferroptosis is a new form of regulated cell death and targeting ferroptosis provides a novel therapeutic approach for human cancers. Verteporfin (VP) has been identified as a Yes-associated protein (YAP) inhibitor for treatment of several human cancers. However, it remains unclear whether VP exerts anticancer activity by inducing ferroptosis in ESCC cells. In the current study, we found that VP reduced cell viability and led to cell death in ESCC cell lines (KYSE150 and KYSE30) by inhibiting YAP expression. Subsequently, the findings revealed that VP treatment triggered significant ferroptosis events, including accumulation of Fe 2+ , reactive oxygen species (ROS) and malondialdehyde (MDA), reduction of mitochondrial membrane potential (MMP), glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. Further study showed that the effects of ESCC cell proliferation and death caused by VP could be reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, VP enhanced the chemosensitivity of ESCC resistant cells to paclitaxel (PTX). And VP combined with PTX can synergistically inhibit cell proliferation and induce cell death by triggering ferroptosis of PTX-resistant cells. All these data suggested that VP suppressed ESCC cell survival and reversed resistance to PTX through inducing ferroptosis, which may provide a promising therapeutic strategy for ESCC.