Enhanced Anti-cancer Efficacy of Sorafenib and Pioglitazone via VEGF Inhibition in DMBA-Induced Breast Cancer Model.

Abstract

Breast cancer remains the most prevalent cancer among women and a significant cause of mortality, partly due to treatment resistance and adverse effects. Sorafenib, a tyrosine kinase inhibitor, and Pioglitazone, a PPAR-γ agonist, exhibit anti-cancer properties. This study explores improved anti-cancer effects of combination of Sorafenib and Pioglitazone for breast cancer treatment. Protein-ligand molecular docking was performed to identify interactions of both drugs with various proteins. Cytotoxic effects of Sorafenib and Pioglitazone, individually and in combination, were evaluated on MCF-7 cells using MTT assay. DMBA-induced breast cancer model in female Sprague-Dawley rats assessed tumor volume, survival rates, oxidative stress markers, cytokines, tumor markers, and histopathology. Rats were divided into six groups, including control, individual treatments, combination therapy, and a doxorubicin standard group. Sorafenib demonstrated dose-dependent cytotoxicity. Pioglitazone exhibited limited cytotoxic effects when used alone but showed significant cytotoxicity when combined with Sorafenib. Combination therapy resulted in reduced tumor volume, enhanced survival rates, and restored body weight in DMBA-induced treatment animals. It significantly lowered oxidative stress parameters and pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, as well as phosphorylated Akt levels. It inhibited tumor angiogenic markers VEGFR2 and VEGFR3 and promoted tumor suppressor p53 levels. Histopathological analysis confirms a reduction in tumor cell invasion and inflammation. The combination of Sorafenib and Pioglitazone exhibited enhanced anti-cancer effects by suppressing oxidative stress, inflammatory markers, pAkt, VEGF2, and VEGF3, as well as upregulating p53 levels, highlighting the promising potential of this combination for breast cancer treatment.