Arachidin-1, a Prenylated Stilbenoid from Peanut, Enhances the Anticancer Effects of Paclitaxel in Triple-Negative Breast Cancer Cells

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is an aggressive type of cancer that is challenging to treat due to the lack of hormonal receptors used to target cancer cells; due to this, TNBC patients have high mortality rates. Plant-derived compounds are being sought as potential adjuvants for common chemotherapy drugs, such as paclitaxel (Pac). To this end, this research aimed to study the prenylated stilbenoid arachidin-1 (A-1) as a potential adjuvant for Pac. Here, the cytotoxic and apoptosis induction effects of A-1 alone and combined with Pac were investigated in 2D TNBC cell cultures and a 3D TNBC spheroid model. The results illustrated that A-1, in low micromolar concentrations, combined with Pac, inhibited cell proliferation, induced apoptosis, and reduced spheroid growth. Furthermore, our findings suggest that A-1 combined with Pac has the potential to be developed as a novel plant-derived treatment for TNBC. ABSTRACT: Triple-negative breast cancer (TNBC) is one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. To this end, the cytotoxic effects of the prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3), and non-prenylated resveratrol (RES) were evaluated in human TNBC cell lines as potential adjuvants for paclitaxel (Pac). A-1, alone or in combination with Pac, showed the highest cytotoxicity in TNBC cells. Apoptosis was further evaluated by measuring key apoptosis marker proteins, cell cycle arrest, and intracellular reactive oxygen species (ROS) generation. Furthermore, the cytotoxic effect of A-1 combined with Pac was also evaluated in a 3D spheroid TNBC model. The results showed that A-1 decreased the Pac IC(50) approximately 2-fold in TNBC cells. The synergistic combination of A-1 and Pac arrested cells in G2/M phase and activated p53 expression. In addition, the combined treatment increased intracellular ROS generation and induced apoptosis. Importantly, the combination of A-1 with Pac inhibited TNBC spheroid growth. Our results demonstrated that A-1 in combination with Pac inhibited cell proliferation, induced apoptosis through mitochondrial oxidative stress, and reduced TNBC spheroid growth. These findings underscore the impactful effects of the prenylated stilbenoid A-1 as a novel adjuvant for Pac chemotherapy in TNBC treatment.