The ponatinib/gossypol novel combination provides enhanced anticancer activity against murine solid Ehrlich carcinoma via triggering apoptosis and inhibiting proliferation/angiogenesis

Theodor Bilharz Research Institute

Bibliographic Information

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

Journal: Toxicology and Applied Pharmacology

Publisher: Academic Press Inc.

Publication Date: December 2021

Volume / Issue: Volume 432

Article No.: 115767

ISSN: 0041008X

DOI: 10.1016/j.taap.2021.115767

Scopus: View on Scopus

PubMed: 34699866

Document Type: Article

Authors and Affiliations

El-Lakkany N.M., Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Giza, 12411, Egypt; 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

Abstract

The search for new antitumor agents or combinations that are more effective and, hopefully, provide fewer health hazards is ongoing. Therefore, this study investigated the efficacy of a novel combination of ponatinib, a multi-targeted tyrosine kinase inhibitor, and the natural phytochemical gossypol against murine solid Ehrlich carcinoma. Six groups of ten mice each received vehicle (I), ponatinib in doses of 10 and 15 mg/kg (II, III) respectively, gossypol in a dose of 4 mg/kg (IV), and ponatinib (10 or 15 mg/kg) in combination with gossypol (4 mg/kg; V, VI). All treatments started on the 12th post-Ehrlich ascites carcinoma (EAC) implantation day and were administered intraperitoneally in daily doses for 3 weeks. Treatment of EAC-bearing mice with ponatinib/gossypol combination improved anticancer efficacy over either drug alone, as demonstrated by greater decreases in tumor weight and volume, and ponatinib (10 mg/kg)/gossypol combination was more efficient than ponatinib (15 mg/kg). Mechanistically, the ponatinib/gossypol combination significantly increased apoptotic markers p53, Bax, and caspase-9 while decreasing anti-apoptotic marker Bcl-2. Furthermore, it greatly decreased proliferative and angiogenic markers, FGFR4 and VEGF, respectively. Histopathology revealed a significant decline in neoplastic cells, the majority of which have necrotic changes and numerous apoptotic bodies, as well as a decrease in mitotic figures and tumor giant cells, indicating the capacity to suppress cancer proliferation/persistence. Overall, gossypol could be used as an adjuvant medication for ponatinib in cancer treatment, possibly leading to successful dose reductions and fewer side effects; however, further research is needed before a clinical application could be feasible. © 2021 Elsevier Inc.

Keywords

Angiogenesis; Apoptosis; FGFR4; Gossypol; Ponatinib; Solid Ehrlich tumor; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Proliferation; Female; Imidazoles; Mice; Neovascularization, Pathologic; Oxidative Stress; Pyridazines; Receptor, Fibroblast Growth Factor, Type 4; Signal Transduction; Tumor Burden; Vascular Endothelial Growth Factor A; caspase 9; fibroblast growth factor receptor 4; gossypol acetic acid; protein Bax; protein bcl 2; protein p53; vasculotropin; angiogenesis inhibitor; antineoplastic agent; apoptosis regulatory protein; Fgfr4 protein, mouse; imidazole derivative; pyridazine derivative; vascular endothelial growth factor A, mouse; vasculotropin A; adult; animal experiment; animal model; animal tissue; antiangiogenic activity; antineoplastic activity; Article; cancer inhibition; controlled study; dose response; drug dose comparison; drug efficacy; drug mechanism; Ehrlich ascites tumor; giant cell; histopathology; mitosis; mouse; nonhuman; tumor volume; tumor weight; animal; drug effect; metabolism; neovascularization (pathology); pathology; tumor cell line

Citation Information

Scopus Citations: 15

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