5-FU and the Dietary Flavonoid Carvacrol: a Synergistic Combination That Induces Apoptosis in MCF-7 Breast Cancer Cells

Along with the benefits of chemotherapy in the treatment of breast cancer, the side effects of these drugs along with drug resistance make their use complicated. One of the solutions to overcome this problem is the use of herbal products and combination therapy. In this research, we try to investigate the effects of carvacrol, a monoterpene flavonoid, in combination with the chemotherapy drug 5-FU. Combination index method was used for the drug-drug interactions analysis based on the Chou and Talalay method and the data from MTT assays. Apoptosis was assessed by the ELISA cell death method. P-glycoprotein expression was evaluated at the gene level by Real-time PCR. Here, we described the first experimental evidence for the existence of synergism between carvacrol and 5-FU in the in vitro model of breast cancer. MTT assay results showed combination treatment of the cells with carvacrol and 5-FU decreased 5-FU concentrations significantly. Incubation of the cells with carvacrol neutralized P-glycoprotein overexpression in qPCR assay (P ≤ 0.05). Compared with adding verapamil (a P-glycoprotein inhibitor) to 5-FU, the combination of carvacrol and 5-FU caused a further increase in the percentage of apoptotic cells when the cells were treated with both agents. Our results suggest that carvacrol can downregulate P-gp expression and combination therapy with carvacrol and 5-FU is considered a novel approach to improve the efficacy of chemotherapeutics in cancer patients with high P-glycoprotein expression.