Triple-negative breast cancer (TNBC) is unresponsive to typical hormonal treatments, causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. The goal of this study was to assess cytotoxicity and apoptosis mechanisms of prenylated stilbenoids in TNBC cells. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3) are analogs of resveratrol (RES) produced in peanut upon biotic stress. The anticancer activity of A-1 and A-3 isolated from peanut hairy root cultures was determined in TNBC cell lines MDA-MB-231 and MDA-MB-436. After 24 h of treatment, A-1 exhibited higher cytotoxicity than A-3 and RES with approximately 11-fold and six-fold lower IC50, respectively, in MDA-MB-231 cells, and nine-fold and eight-fold lower IC50, respectively, in MDA-MB-436 cells. A-1 did not show significant cytotoxicity in the non-cancerous cell line MCF-10A. While A-1 blocked cell division in G2-M phases in the TNBC cells, it did not affect cell division in MCF-10A cells. Furthermore, A-1 induced caspase-dependent apoptosis through the intrinsic pathway by activating caspase-9 and PARP cleavage, and inhibiting survivin. In conclusion, A-1 merits further research as a potential lead molecule for the treatment of TNBC.

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 IC50 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.

Breast cancer is the most prevalent type of cancer among women worldwide. Triple‐negative breast cancer (TNBC) is unresponsive to typical hormonal treatments causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. This study aims to examine the role of prenylated stilbenoids as an adjuvant for paclitaxel, a chemotherapeutic drug with severe side effects. To produce prenylated stilbenoids, hairy root cultures of peanut were co‐treated with elicitors and further purified via semi‐preparative high performance liquid chromatography. The cytotoxicity of prenylated stilbenoids was studied in TNBC cell lines MDA‐MB‐231 and MDA‐MB‐436 and the non‐cancerous cell line MCF‐10A. At low micromolar concentrations, the prenylated stilbenoid arachidin‐1 showed no significant cytotoxicity in the non‐cancerous cell line, whereas it was cytotoxic in the TNC cell lines. High cytotoxicity levels correlated with increased levels of the apoptosis markers caspase‐3 and caspase‐7. Arachidin‐1 also decreased the IC50 of paclitaxel by approximately 4‐fold and blocked cell division in S and G2‐M phases in the TNBC cells. Furthermore, paclitaxel combined with arachidin‐1 induced apoptosis through the intrinsic pathway by activation of caspase‐9. This highlights the significance of continuing research with prenylated stilbenoids in TNBC. Current studies focus on elucidating the signaling pathways affected by these compounds in TNBC cells to advance our understanding of the anticancer mechanisms of these natural products.