Hu Guang-Fu, Wang Cheng, Hu Guang-Xia, Wu Ge, Zhang Chengjiao, Zhu Wei, Chen Cong, Gu Yutong, Zhang Hongwei, Yang Zi'ang
Department of Breast Surgery, Huangpu Branch, Shanghai Ninth People's Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Department of Pathology, Binzhong People's Hospital, Binzhong 256600, China.
Ann Transl Med. 2020 Mar;8(6):336. doi: 10.21037/atm.2020.02.110.
The bone-derived insulin-like growth factor I (IGF-1) and its receptor IGF-1R play a crucial role in promoting the survival and proliferation of cancer cells, and have thus been considered as prime targets for the development of novel antitumor therapeutics.
By using the MDA-MB-231BO cell line, which is the osteotropic metastatic variant of the human breast adenocarcinoma cell line MDA-MB-231, and an model of breast cancer metastasis to bone, the current study evaluated the effect of AZD3463, an IGF-1R inhibitor, used alone or in combination with zoledronic acid (ZA), on the regulation of IGF-1R associated signal pathway and treatment of bone metastases (BM). Cell proliferation and invasion were measured by methyl thiazolyl tetrazolium (MTT) and Transwell assay respectively. Apoptotic cell number was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL).
AZD3463 was shown to alleviate IGF-1R phosphorylation promoted by IGF-1 treatment in MDA-MB-231BO cells in a dose-dependent manner. In both the cells and the mouse model, 5 nM of AZD3463 stimulated cell apoptosis and suppressed proliferation on a level similar to that of 100 µM of ZA. Remarkably, the combined use of AZD3463 and ZA exhibited a synergistic effect and greater antitumor activity compared to when they were employed individually. Mechanistic investigations indicated that the apoptosis-inducing activity of AZD3463 could be associated to its role in the activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway.
These findings suggested that AZD3463 could serve as a promising therapeutic molecule for treating BM in breast cancer patients, particularly when applied in conjunction with ZA or other antitumor agents.
骨源性胰岛素样生长因子I（IGF-1）及其受体IGF-1R在促进癌细胞存活和增殖中起关键作用，因此被视为新型抗肿瘤治疗药物开发的主要靶点。
本研究使用人乳腺腺癌细胞系MDA-MB-231的骨转移性变体MDA-MB-231BO细胞系以及乳腺癌骨转移模型，评估IGF-1R抑制剂AZD3463单独使用或与唑来膦酸（ZA）联合使用对IGF-1R相关信号通路的调节作用以及对骨转移（BM）的治疗效果。分别通过甲基噻唑基四氮唑（MTT）法和Transwell实验检测细胞增殖和侵袭能力。通过末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记法（TUNEL）检测凋亡细胞数量。
结果显示，AZD3463能以剂量依赖的方式减轻IGF-1处理促进的MDA-MB-231BO细胞中IGF-1R磷酸化。在细胞和小鼠模型中，5 nM的AZD3463刺激细胞凋亡并抑制增殖，其水平与100 μM的ZA相似。值得注意的是，与单独使用时相比，AZD3463和ZA联合使用表现出协同效应和更强的抗肿瘤活性。机制研究表明，AZD3463的诱导凋亡活性可能与其在磷酸肌醇3激酶（PI3K）-Akt信号通路激活中的作用有关。
这些发现表明，AZD3463可能是治疗乳腺癌患者骨转移的有前景的治疗分子，特别是与ZA或其他抗肿瘤药物联合应用时。
