Xie Wei, Zhang Yan, Zhang Shiwei, Wang Fengxian, Zhang Kunchi, Huang Yanjuan, Zhou Zhaoli, Huang Gang, Wang Jin
School of Pharmacy, Shanghai University of Medicine and Health Sciences Shanghai 201318, P. R. China.
Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences Shanghai 201318, P. R. China.
Am J Cancer Res. 2019 Aug 1;9(8):1796-1814. eCollection 2019.
Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), was used in combination with traditional chemotherapy as the first line treatment for metastatic colorectal cancer (mCRC), non-small cell lung cancer (NSCLC) and advanced ovarian cancer. However, it shows limited efficacy for human triple-negative breast cancer (TNBC). Bevacizumab shows potent anti-angiogenesis activity, meanwhile, it also increases invasive and metastatic properties of TNBC cells by activiting Wnt/β-Catenin pathway. To overcome this problem, and fully utilize its potency against cancer, further synergistic strategy is recommended to be developed, especially the concurrent use with those Wnt-targeting agents. Here, by screening a small library of traditional Chinese medicine, we identified a Chinese herb derived Oxymatrine, which could target Wnt/β-Catenin signaling and compromise the oncogenic effects of Bevacizumab. Bevacizumab was validated to induce epithelial-mesenchymal cell transformation (EMT) and cancer stem-like properties of TNBC cells in hypoxia/nutritional stress environment. On the contrary, Oxymatrine reversed the EMT phenotype and depleted the subpopulation of TNBC stem cells induced by Bevacizumab. Oxymatrine enhanced the anti-tumor effects of Bevacizumab , and holded the potential of reducing the risk of relapse and metastasis by impairing the self-renewal ability of TNBC stem cells. The underlying mechanism was elucidated: Bevacizumab stimulated Wnt/β-Catenin signaling pathway, and Oxymatrine could compromise this effect. On this foundation, factoring into the satisfactory anti-angiogenic activity and low toxicity, Oxymatrine is a good candidate for the synergistic therapy together with Bevacizumab for the treatment of TNBC.
贝伐单抗是一种靶向血管内皮生长因子A（VEGF-A）的单克隆抗体，曾与传统化疗联合用于转移性结直肠癌（mCRC）、非小细胞肺癌（NSCLC）和晚期卵巢癌的一线治疗。然而，它对人类三阴性乳腺癌（TNBC）的疗效有限。贝伐单抗具有强大的抗血管生成活性，同时，它还通过激活Wnt/β-连环蛋白通路增加TNBC细胞的侵袭和转移特性。为克服这一问题，并充分发挥其抗癌效力，建议制定进一步的协同策略，尤其是与那些靶向Wnt的药物联合使用。在此，通过筛选一个小型中药库，我们鉴定出一种中药衍生的氧化苦参碱，它可以靶向Wnt/β-连环蛋白信号并抵消贝伐单抗的致癌作用。已证实贝伐单抗在缺氧/营养应激环境中可诱导TNBC细胞发生上皮-间质细胞转化（EMT）和癌症干细胞样特性。相反，氧化苦参碱逆转了EMT表型，并减少了由贝伐单抗诱导的TNBC干细胞亚群。氧化苦参碱增强了贝伐单抗的抗肿瘤作用，并有可能通过削弱TNBC干细胞的自我更新能力来降低复发和转移风险。其潜在机制得以阐明：贝伐单抗刺激Wnt/β-连环蛋白信号通路，而氧化苦参碱可以抵消这种作用。在此基础上，考虑到氧化苦参碱令人满意的抗血管生成活性和低毒性，它是与贝伐单抗联合用于治疗TNBC的协同治疗的良好候选药物。
