The ponatinib/gossypol novel combination provides enhanced anticancer activity against murine solid Ehrlich carcinoma
Naglaa M El-Lakkany1, Hadeel H Elkattan1, Alaa E Elsisi2
1Department of Pharmacology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, Giza 12411, 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.
Insights
The combination of ponatinib and gossypol shows enhanced anticancer efficacy against Ehrlich carcinoma in mice. This novel drug combination effectively reduced tumor growth and increased cancer cell death, suggesting potential for improved cancer therapies.
Area of Science:
- Oncology
- Pharmacology
- Natural Product Chemistry
Background:
- The continuous search for more effective and safer antitumor agents is crucial in cancer therapy.
- Novel drug combinations are being explored to overcome limitations of single-agent treatments.
- Tyrosine kinase inhibitors and natural phytochemicals represent promising avenues for cancer drug development.
Purpose of the Study:
- To investigate the efficacy of a novel combination of ponatinib and gossypol against murine solid Ehrlich carcinoma.
- To evaluate the mechanistic effects of the ponatinib/gossypol combination on cancer cell apoptosis, proliferation, and angiogenesis.
- To determine if gossypol can act as an adjuvant to ponatinib, potentially reducing dosage and side effects.
Main Methods:
- Murine solid Ehrlich carcinoma model was established.
- Mice were treated with vehicle, ponatinib alone, gossypol alone, or a combination of ponatinib and gossypol.
- Tumor weight, volume, apoptotic markers (p53, Bax, caspase-9, Bcl-2), proliferative (FGFR4), and angiogenic (VEGF) markers were assessed.
- Histopathological analysis was performed to evaluate neoplastic cell changes, necrosis, and mitotic figures.
Main Results:
- The ponatinib/gossypol combination significantly reduced tumor weight and volume compared to monotherapy.
- The combination therapy markedly increased apoptotic markers and decreased anti-apoptotic markers.
- Ponatinib/gossypol treatment significantly reduced proliferative and angiogenic markers (FGFR4, VEGF).
- Histopathology confirmed decreased neoplastic cells, increased necrosis and apoptosis, and reduced mitotic figures.
Conclusions:
- The combination of ponatinib and gossypol demonstrates superior anticancer efficacy against Ehrlich carcinoma in mice.
- Gossypol can potentially serve as an adjuvant to ponatinib, enhancing therapeutic outcomes and possibly reducing side effects.
- Further clinical research is warranted to validate the efficacy and safety of this combination for human cancer treatment.
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