1. PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3β and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma.
- Author
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Cao J, Zeng K, Chen Q, Yang T, Lu F, Lin C, Zhan J, Ma W, Zhou T, Huang Y, Luo F, and Zhao H
- Subjects
- Humans, Animals, Mice, Nasopharyngeal Carcinoma drug therapy, Nasopharyngeal Carcinoma metabolism, Glycogen Synthase Kinase 3 beta metabolism, Gemcitabine, Signal Transduction, TOR Serine-Threonine Kinases metabolism, Protein Kinase Inhibitors pharmacology, Phosphoinositide-3 Kinase Inhibitors pharmacology, MTOR Inhibitors, Angiogenesis Inhibitors pharmacology, Cell Line, Tumor, Cell Proliferation, Apoptosis, Proto-Oncogene Proteins c-akt metabolism, Phosphatidylinositol 3-Kinases metabolism, Nasopharyngeal Neoplasms pathology, STAT3 Transcription Factor
- Abstract
End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3β and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC., (© 2024. The Author(s).)
- Published
- 2024
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