Diallyl Trisulfide Enhances Doxorubicin Chemosensitivity by Inhibiting the Warburg Effect and Inducing Apoptosis in Breast Cancer Cells

Breast cancer is the leading cause of cancer-related mortality among women. Doxorubicin (DOX) is the major chemotherapeutic agent for breast cancer treatment, but its efficacy is hindered by chemoresistance and dose-dependent toxicity. Overcoming these challenges requires novel therapeutic strategies that enhance DOX sensitivity while minimizing its adverse effects. Diallyl trisulfide (DATS), a natural organosulfur compound derived from garlic, has demonstrated anticancer potential, yet its role in enhancing DOX chemosensitivity remains unclear. The anticancer potential of the combination treatment was investigated using MTT, glucose uptake, and lactate production assays, Western blot, flow cytometry, TUNEL staining, transfection, and an <i>in vivo</i> orthotopic tumor model in NOD/SCID mice. DATS and DOX combination treatment synergistically inhibited the viability of breast cancer cell lines. The combination treatment significantly reduced glucose uptake and lactate production while downregulating key glycolytic regulators, including GLUT1, LDHA, and HIF-1α. These metabolic alterations were associated with enhanced apoptosis, as evidenced by elevated expression of Bax, cleaved caspase-3, and PARP1, along with downregulation of anti-apoptotic proteins Bcl-2 and Bcl-xL. TUNEL and Annexin V-FITC/PI assays further confirmed apoptosis induction in response to combination therapy. <i>In vivo</i> studies using an orthotopic MDA-MB-231 xenograft model revealed that DATS and DOX combination treatment significantly suppressed tumor growth while reducing systemic toxicity, as indicated by stable body weight and minimal adverse effects. Overall, our findings show that DATS enhances DOX sensitivity by inhibiting the Warburg effect and promoting apoptosis in breast cancer cells. These findings suggest that the DOX-DATS combination represents a promising strategy to improve chemotherapeutic efficacy in breast cancer.