Combination of resveratrol and piperine to target doxorubicin resistance in breast cancer: An in vitro and in vivo study

One of the biggest causes of death worldwide is cancer, which poses a serious threat to healthcare systems all over the world. Triple-negative breast cancer (TNBC), in particular, presents substantial clinical challenges because it does not express Human Epidermal Growth Factor Receptor 2 (HER2) or hormone receptors. Despite concerns about early recurrence and drug resistance, chemotherapy, particularly anthracyclines like Doxorubicin (DOX), remains the mainstay of treatment for TNBC patients. This research investigates the possibility of using natural products, especially piperine (PIP) and resveratrol (RES), to overcome DOX resistance. PIP and RES have shown anticancer effects via various pathways, such as inducing apoptosis and controlling the cell cycle. In this research, in vitro experiments showed that RES and PIP inhibit cell growth in a dose-dependent manner using triple-negative parent mouse mammary breast cancer cells and DOX resistance cells (EMT-6/P and EMT-6/DOX). RES in EMT-6/P cells showed an IC50 value of 146.511 ± 5.35 μM, and in EMT-6/DOX cells, it was 88.635 ± 29.507 μM. In the same way, PIP was found to have IC50 values of 148.819 ± 14.317 and 9.375 μM in the triplicate trials in EMT-6/P and EMT-6/DOX, respectively. Furthermore, on both cell lines, the combination demonstrated very strong synergistic effects; noticeably lower doses were needed for the combined treatment to reduce cell viability by 50%. The IC50 values for the combination treatments of RES and PIP were found to be < 2.289 µM and < 2.325 µM in EMT-6/P cells, respectively, with values < 0.348 µM and 0.243 ± 0.142 µM in EMT-6/DOX cells. The in vivo experiment conducted on Balb/C females indicated that mice bearing EMT-6/Dox cells and treated with the combination of RES and PIP had the highest cure percentage; however, this treatment showed mild toxicity. The study clarifies the potential synergistic activity between PIP and RES in combating DOX-resistant TNBC cells. These findings highlight the significance of investigating natural products as supplemental therapies in cancer treatment and provide insights into new treatment approaches. While the combination shows promise as a therapeutic option for treating breast cancer, especially in cases of DOX resistance, further investigation is needed.