Evaluation of Combination Therapy of Naringenin and Metformin in Doxorubicin Chemotherapy against in vitro and in vivo Models of Breast Carcinoma

Abstract

Introduction: Breast cancer is the most common malignancy in women around the world. The present work is aimed to evaluate the potential of naringenin and metformin concomitant addition with doxorubicin chemotherapy against in vitro and in vivo breast carcinoma models. newlineMethods: Cell viability was measured by MTT assay using breast cancer cell lines (MDA-MB-231 and 4T1). The antitumor potential of drugs under the study was evaluated against methylnitrosourea (MNU)-induced breast carcinoma in rats, MDA-MB-231 xenograft model in athymic nude mice and finally 4T1 cells-induced orthotopic mouse model of breast cancer. The efficacy and safety of single-drug treatment and combination treatment were evaluated using different parameters in selected animal models of breast carcinoma. newlineResults: The use of naringenin and metformin together with doxorubicin, have shown a significant increase in cytotoxicity when compared with the same concentration of doxorubicin alone in MDA-MB-231 cells and 4T1 cells in vitro. There was a marked reduction in tumor weight and an observed decrease in tumor multiplicity by naringenin and metformin concomitant addition with doxorubicin against MNU-induced breast carcinoma. Likewise, naringenin and metformin with doxorubicin showed a significant reduction of tumor volume and tumor weight as compared to the same dose of doxorubicin alone in MDA-MB-231 xenograft model and 4T1 cells-induced orthotopic mouse model, suggesting combination treatment enhanced antitumor activity in vivo. Besides, HandE and Ki-67 staining of tumor biopsies showed enhancement of the antitumor activity via increasing necrosis and inhibiting cell proliferation respectively. Hematological parameters, body weight, survival data, cytokines levels and cardiac biomarker levels presented remarkable safety of combination treatment without compromising efficacy using 50% lower dose of doxorubicin, compared to the large dose of doxorubicin alone. newlineConclusion: These results demonstrate that naringenin and metformin enhanced the anti