Chang Chun-Ming, Wang Wei-Jan, Mhone Thomas G, Ho Wen-Kun, Chen Chih-Jung, Ng Shawn Shang-Chuan, Li Chi-Cheng, Kuo Chia-Hua, Huang Chih-Yang, Kuo Wei-Wen
Department of General Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
J Cancer. 2025 Jul 11;16(11):3283-3295. doi: 10.7150/jca.113578. eCollection 2025.
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 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. 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.
乳腺癌是女性癌症相关死亡的主要原因。阿霉素（DOX）是乳腺癌治疗的主要化疗药物，但其疗效受到化疗耐药性和剂量依赖性毒性的阻碍。克服这些挑战需要新的治疗策略，既能提高DOX敏感性，又能将其副作用降至最低。二烯丙基三硫化物（DATS）是一种源自大蒜的天然有机硫化合物，已显示出抗癌潜力，但其在增强DOX化疗敏感性方面的作用仍不清楚。使用MTT、葡萄糖摄取和乳酸生成测定、蛋白质免疫印迹法、流式细胞术、TUNEL染色、转染以及NOD/SCID小鼠原位肿瘤模型研究了联合治疗的抗癌潜力。DATS与DOX联合治疗协同抑制乳腺癌细胞系的活力。联合治疗显著降低了葡萄糖摄取和乳酸生成，同时下调了关键的糖酵解调节因子，包括GLUT1、LDHA和HIF-1α。这些代谢改变与细胞凋亡增加有关，Bax、裂解的caspase-3和PARP1表达升高以及抗凋亡蛋白Bcl-2和Bcl-xL下调证明了这一点。TUNEL和Annexin V-FITC/PI测定进一步证实了联合治疗诱导的细胞凋亡。使用原位MDA-MB-231异种移植模型的研究表明，DATS与DOX联合治疗显著抑制肿瘤生长，同时降低全身毒性，体重稳定和不良反应最小表明了这一点。总体而言，我们的研究结果表明，DATS通过抑制乳腺癌细胞中的瓦伯格效应和促进细胞凋亡来增强DOX敏感性。这些发现表明，DOX-DATS联合治疗是提高乳腺癌化疗疗效的一种有前景的策略。
