Zhou Jun-Zhen, Wen Jing-Ya, Xu Xin-Wen, Zhao Na, Tang Jing-Jing, Xiao Ye-Rui, Xiang Le-Yang, Jiang Yue, Jiang Jian-Wei, Hong Hong, Zhang Qing
Department of Breast Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China.
Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, China.
Transl Oncol. 2025 Aug;58:102434. doi: 10.1016/j.tranon.2025.102434. Epub 2025 Jun 1.
Triple-negative breast cancer (TNBC) exhibits the highest recurrence and mortality rates among breast cancer subtypes. Approximately one million TNBC cases are diagnosed worldwide annually. Current clinical treatments, primarily chemotherapy regimens based on paclitaxel and anthracycline, are associated with high recurrence rates and low overall survival rates. Platinum drugs, introduced for TNBC treatment, demonstrated a positive effect; however, their high-dose administration inevitably results in toxic side effects and drug resistance. Therefore, identifying agents that sensitize patients to platinum-based therapies is critical. Analysis of the TCGA database revealed that AKT1 and autophagy are activated in breast cancer, playing crucial roles in malignant behavior. Further investigation demonstrated that CBP activates the AKT pathway in MDA-MB-231 cells, while its combination with LY294002 or Triciribine (inhibitors of the PI3K/AKT pathway), suppresses cell proliferation. However, this combination also activates autophagy, a protective mechanism. Inhibition of autophagy with CQ or Baf A1 further increased the proliferation-inhibitory effects of CBP in MDA-MB-231 cells. Notably, the sesquiterpene lactone EM-2 extracted from Elephantopus mollis H.B.K., significantly inhibited both the AKT and autophagy pathways in TNBC cells, demonstrating superior cellular inhibitory effects compared with other AKT or autophagy inhibitors combined with CBP. When CBP was combined with EM-2, cell survival decreased by approximately 36 % compared with CBP monotherapy, while the apoptosis rate increased by 22.8 % after 48 h. The combination of CBP and EM2 also produced the greatest tumor shrinkage in vivo. Interestingly, the CBP (3 mg/kg) + EM-2 (6 mg/kg) group achieved the same tumor shrinkage, with only one-fifth the amount of CBP compared with the CBP (16 mg/kg) monotherapy group. In other words, low doses of EM-2 combined with CBP produced the same anti-tumor effects as high-dose CBP alone. These findings provide a novel strategy for the treatment of CBP using dual AKT and autophagy inhibitors, highlighting potential clinical applications.
三阴性乳腺癌（TNBC）在乳腺癌亚型中表现出最高的复发率和死亡率。全球每年约有100万例TNBC病例被诊断出来。目前的临床治疗主要是基于紫杉醇和蒽环类药物的化疗方案，其复发率高且总生存率低。用于TNBC治疗的铂类药物显示出积极效果；然而，高剂量给药不可避免地会导致毒副作用和耐药性。因此，识别能使患者对铂类疗法敏感的药物至关重要。对TCGA数据库的分析显示，AKT1和自噬在乳腺癌中被激活，在恶性行为中起关键作用。进一步研究表明，CBP在MDA-MB-231细胞中激活AKT通路，而其与LY294002或曲西立滨（PI3K/AKT通路抑制剂）联合使用时，可抑制细胞增殖。然而，这种联合也会激活自噬，这是一种保护机制。用氯喹或巴弗洛霉素A1抑制自噬可进一步增强CBP对MDA-MB-231细胞的增殖抑制作用。值得注意的是，从地胆草中提取的倍半萜内酯EM-2显著抑制TNBC细胞中的AKT和自噬通路，与其他与CBP联合使用的AKT或自噬抑制剂相比，显示出更强的细胞抑制作用。当CBP与EM-2联合使用时，与CBP单药治疗相比，细胞存活率降低了约36%，而48小时后凋亡率增加了22.8%。CBP与EM2联合使用在体内也产生了最大的肿瘤缩小。有趣的是，CBP（3mg/kg）+EM-2（6mg/kg）组实现了相同的肿瘤缩小，与CBP（16mg/kg）单药治疗组相比，CBP的用量仅为其五分之一。换句话说，低剂量的EM-2与CBP联合使用产生的抗肿瘤效果与高剂量的CBP单独使用相同。这些发现为使用双AKT和自噬抑制剂治疗CBP提供了一种新策略，突出了潜在的临床应用价值。
