Gossypol enhances ponatinib's cytotoxicity against human hepatocellular carcinoma cells by involving cell cycle arrest, p-AKT/LC3II/p62, and Bcl2/caspase-3 pathways

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Elkattan H.H.; Elsisi A.E.; El-Lakkany N.M.

Journal: Toxicology Reports

Publisher: Elsevier Inc.

Publication Date: June 2025

Volume / Issue: Volume 14

Article No.: 101856

ISSN: 22147500

DOI: 10.1016/j.toxrep.2024.101856

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Elkattan H.H., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Giza, 12411, Egypt; Elsisi A.E., Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt; El-Lakkany N.M., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Giza, 12411, Egypt

Abstract

Despite significant breakthroughs in frontline cancer research and chemotherapy for hepatocellular carcinoma (HCC), many of the suggested drugs have high toxic side effects and resistance, limiting their clinical utility. Exploring potential therapeutic targets or novel combinations with fewer side effects is therefore crucial in combating this dreadful disease. The current study aims to use a novel combination of ponatinib and gossypol against the HepG2 cell line. Cell survival, FGF19/FGFR4, apoptotic and autophagic cell death, and synergistic drug interactions were assessed in response to increasing concentrations of ponatinib and/or gossypol treatment. Research revealed that ponatinib (1.25–40 μM) and gossypol (2.5–80 μM) reduced the viability of HepG2 cells in a way that was dependent on both time and dose. Ponatinib's anti-proliferation effectiveness was improved synergistically by gossypol and was associated with a rise in apoptotic cell death, cell cycle blockage during the G0/G1 phase, and suppression of the FGF19/FGFR4 axis. Furthermore, the ponatinib/gossypol combination lowered Bcl-2 and p-Akt while increasing active caspase-3, Beclin-1, p62, and LC3II. This combination, however, had no harm on normal hepatocytes. Overall, gossypol enhanced ponatinib's anticancer effects in HCC cells. Notably, this new combination appears to be potential adjuvant targeted chemotherapy, a discovery that warrants more clinical investigation, in the management of patients with HCC. © 2024 The Authors

Keywords

Apoptosis; Autophagy; Cell cycle arrest; Gossypol; Hepatocellular carcinoma; Ponatinib; alpha actin; autophagy related protein; caspase 3; dimethyl sulfoxide; fibroblast growth factor 19; fibroblast growth factor receptor 4; lipocortin 5; microtuble associated protein light chain 3; penicillin derivative; propidium iodide; protein bcl 2; sequestosome 1; streptomycin; unclassified drug; adjuvant chemotherapy; adolescent; antineoplastic activity; antiproliferative activity; Article; autophagosome; BNL 1ME A.7R.1 cell line; cancer chemotherapy; cancer patient; cell cycle G0 phase; cell death; cell proliferation; cell survival; cell viability; chemiluminescence immunoassay; controlled study; cytotoxicity; drug interaction; enzyme linked immunosorbent assay; flow cytometry; fluorescence activated cell sorting; G2 phase cell cycle checkpoint; gene expression; Hep-G2 cell line; high performance liquid chromatography; human; human cell; IC50; liver cell carcinoma; male; MTT assay; phase contrast microscopy; quantitative analysis; RNA immunoprecipitation; synergistic effect; Western blotting

Citation Information

Scopus Citations: 3

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