Abstract

BackgroundHesperetin (Hst), a citrus flavanone, is widely distributed among citrus fruits, including lemons. Hst has been shown to possess bioactivity as an antioxidant, anti-inflammatory, anti-allergic, hypolipidemic, vasoprotector, and anticancer agent. This study aimed to identify potential combinations of Hst and the chemotherapeutic agent doxorubicin (Dox) as co-chemotherapy agents against 4T1 murine metastatic breast cancer cells.ResultsMTT assay results showed that Hst exhibited cytotoxic effect in 4T1 cells, and its combination with Dox showed a synergistic effect based on the CI value. The combination of Hst and Dox increased G2/M phase cell cycle arrest and apoptosis induction. The combination of Hst and Dox inhibited migration and decreased MMP-9 expression in 4T1 cells.ConclusionIn conclusion, the results of this study show that Hst has potential as a Dox co-chemotherapy against 4T1 cells by inducing G2/M phase cell cycle arrest and apoptosis. More importantly, Hst reduces Dox-induced migration and decreases MMP-9 expression.

Highlights

  • Hesperetin (Hst), a citrus flavanone, is widely distributed among citrus fruits, including lemons

  • Cytotoxicity of Hst and Dox in 4T1 cells The cytotoxicity of Hst and Dox was determined with the MTT assay

  • The combination of Hst and Dox showed an additive effect (Fig. 1b) as indicated by the combination index (CI) value based on Chou and Talalay method, which was between 0.9 and 1.1

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Summary

Introduction

Hesperetin (Hst), a citrus flavanone, is widely distributed among citrus fruits, including lemons. This study aimed to identify potential combinations of Hst and the chemotherapeutic agent doxorubicin (Dox) as co-chemotherapy agents against 4T1 murine metastatic breast cancer cells. Breast cancer is the second most common cancer in the world after lung cancer, with an incidence rate of 11.9%. In 2012, about 30% of the 1.7 million patients diagnosed in 140 countries died from breast cancer [1]. The main cause of death in patients with breast cancer is cancer metastasis, which is a series of complex events that characterize malignancy in cancer cells [2]. Doxorubicin (Dox) is the most common chemotherapy agent used for breast cancer therapy [3, 4]. Dox stimulates TGF-β signaling and increases metastasis in breast

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