Synergistic combination of the beta-3 antagonist SR59230A with common chemotherapeutic drugs and target therapies in cancer and endothelial cells

β3-adrenergic receptors (β3-ARs) are increasingly recognized as modulators of tumor progression and treatment resistance across multiple cancer types. SR59230A, a selective β3-AR antagonist, has shown preclinical antitumor activity through mechanisms involving mitochondrial reactivation, reactive oxygen species (ROS) production, and antiangiogenic effects. Based on this premise, this study aimed to investigate the in vitro synergistic effects of SR59230A combined with standard chemotherapeutics or targeted therapies in various human cancer cell lines (glioblastoma, melanoma, triple-negative breast cancer, anaplastic thyroid carcinoma) and endothelial cells (HUVECs). Cells were treated with SR59230A alone or in fixed-ratio combinations with temozolomide, paclitaxel, vemurafenib, lenvatinib, or sorafenib. Drug interactions were quantified using the Chou–Talalay method and validated with the Loewe additivity model. SR59230A exhibited dose-dependent antiproliferative activity, particularly in HUVECs and thyroid carcinoma cells. Synergistic effects were observed in all models, with the strongest synergy in A-2058 melanoma cells (SR59230A + vemurafenib), MDA-MB-231 breast cancer and 8505C thyroid carcinoma cells (SR59230A + paclitaxel), U-87 glioblastoma cells (SR59230A + temozolomide), and HUVECs (SR59230A + lenvatinib or sorafenib). Dose Reduction Index (DRI) values confirmed the potential to lower cytotoxic drug doses while preserving efficacy. These findings suggest that β3-AR antagonism via SR59230A may enhance the efficacy of conventional and targeted anticancer agents through multimodal mechanisms. The consistent synergistic effects across diverse tumor types support further investigation of β3-AR blockade as a promising strategy to overcome resistance and optimize cancer therapy.