Combinations of PRI-724 Wnt/β-Catenin Pathway Inhibitor with Vismodegib, Erlotinib, or HS-173 Synergistically Inhibit Head and Neck Squamous Cancer Cells

• Published in: International journal of molecular sciences Vol. 24; no. 13; p. 10448
• Main Authors: Kleszcz, Robert, Frąckowiak, Mikołaj, Dorna, Dawid, Paluszczak, Jarosław
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.06.2023; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Annexin V; Antimitotic agents; Antineoplastic agents; Apoptosis; beta Catenin - metabolism; Biological activity; Cancer; Cancer cells; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cell Proliferation; Cell viability; Combinatorial analysis; Epidermal growth factor; Epidermal growth factor receptors; Epigenetics; ErbB Receptors - metabolism; erlotinib; Erlotinib Hydrochloride - pharmacology; Flow cytometry; Head & neck cancer; Head and Neck Neoplasms - drug therapy; hedgehog pathway; Hedgehog protein; Hedgehog Proteins - metabolism; Humans; Hypopharynx; Inhibitors; Kinases; Ligands; Mutation; Oct-4 protein; Pharmaceutical industry; Phosphatidylinositol 3-Kinases - metabolism; PRI-724; Propidium iodide; Proteins; Signal transduction; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Stem cells; Tongue; Tumors; vismodegib; Wnt pathway; Wnt protein; Wnt Signaling Pathway; β-Catenin; Poland; United States; Germany; β-catenin; hedgehog pathway; head and neck cancer; Wnt pathway; erlotinib; HS-173; synergism; vismodegib; PRI-724; cancer stem cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241310448

The Wnt/β-catenin, EGFR, and PI3K pathways frequently undergo upregulation in head and neck squamous carcinoma (HNSCC) cells. Moreover, the Wnt/β-catenin pathway together with Hedgehog (Hh) signaling regulate the activity of cancer stem cells (CSCs). The aim of this study was to investigate the effects of the combinatorial use of the Wnt/β-catenin and Hh pathway inhibitors on viability, cell cycle progression, apoptosis induction, cell migration, and expression of CSC markers in tongue (CAL 27) and hypopharynx (FaDu) cancer cells. Co-inhibition of Wnt signaling with EGFR or PI3K pathways was additionally tested. The cells were treated with selective inhibitors of signaling pathways: Wnt/β-catenin (PRI-724), Hh (vismodegib), EGFR (erlotinib), and PI3K (HS-173). Cell viability was evaluated by the resazurin assay. Cell cycle progression and apoptosis induction were tested by flow cytometric analysis after staining with propidium iodide and Annexin V, respectively. Cell migration was detected by the scratch assay and CSC marker expression by the R-T PCR method. Mixtures of PRI-724 and vismodegib affected cell cycle distribution, greatly reduced cell migration, and downregulated the transcript level of CSC markers, especially encoding OCT4. Combinations of PRI-724 with erlotinib or HS-173 were more potent in inducing apoptosis.