Combining naringenin and metformin with doxorubicin enhances anticancer activity against triple-negative breast cancer in vitro and in vivo

Abstract

Triple-negative breast cancer (TNBC) grows fast and represents poor prognosis and management. This work is aimed to determine the effect of concomitant use of naringenin and metformin with doxorubicin chemotherapy using in vitro and in vivo breast carcinoma models. Cell viability and xenograft study were performed using TNBC cell lines. 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. In the xenograft mouse model, a significant reduction of tumor volume and tumor weight was observed in contrast to a similar dose of doxorubicin alone; suggesting combining treatment enhanced antitumor activity in vivo. Besides, H&E and Ki-67 staining of tumor biopsies showed enhancement of the antitumor activity via increasing necrosis and inhibiting cell proliferation respectively. Additionally, there was no marked change observed in the organ weights, blood glucose, cardiac histology and cardiac Troponin I levels under the study treatment groups. The beneficial effects of using both the naringenin and metformin along with the lower dose of doxorubicin were evident from the reduced dose-related body weight loss and increase in cytokines (TNF-α and IL-1β) compared to a large dose of doxorubicin alone. Thus, naringenin and metformin combination with doxorubicin found useful as an adjunct therapy to improve the effectiveness of doxorubicin at the lower dose against the breast carcinoma.