Combination Treatment with Docetaxel and Phytol or Thymol additively Inhibits Proliferation of Breast Cancer Cells and Down Regulate Expression of Cancer Stem Cell Markers

Breast cancer stem cells are responsible for breast cancer tumorigenesis, metastasis, drug resistance and relapse. Involvement of phytochemicals in targeting breast cancer stem cells provides significant contribution in treatment of breast cancer. We evaluated inhibitory effects of docetaxel and its combination with phytol or thymol on proliferation of breast cancer MCF-7 cells and down-regulation of some cancer stem cell markers. Using MTT assay, docetaxel, phytol and thymol showed cytotoxic activity with IC₅₀ values 20.88, 39 and 642 µM respectively. In the presence of phytol and thymol, IC₅₀ of docetaxel was diminished to 11.30 and 12.1 µM. Combination index calculation and isobologram analysis using CompuSyn software indicated that combination of docetaxel and thymol or phytol at IC₅₀ concentration of each drug generated additive anticancer effect. Real-time quantitative PCR results showed that simultaneous treatment of MCF-7 cells with docetaxel and thymol or phytol showed more efficacy in down-regulation of CD133, CD44, and ABCB1 when compared with docetaxel alone. Moreover, expressions of OCT4 and SOX2 reduced significantly following co- treatment with docetaxel and thymol. In conclusion, purpose of applying multi-drug (Chemotherapy drugs and phytochemical compounds) combinations is to obtain the greatest anti-cancer therapeutic benefit while minimizing toxic side effects. Combination of docetaxel with phytol or thymol evaluated in this study potentiates the cytotoxic properties of docetaxel to kill MCF-7 cancer cells and showed greater effect on reducing expression of CSC markers than docetaxel alone and thus could enhance chemosensitivity to docetaxel and protect cancer patients from cancer recurrence.