Department of Pathology and Laboratory Medicine, and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Department of Medical Imaging, Henan University First Affiliated Hospital, 357 Ximen Street, Kaifeng, Henan, 475001, P.R. China.
Sci Rep. 2020 Apr 24;10(1):7004. doi: 10.1038/s41598-020-64018-z.
The most challenging issue for breast cancer (BC) patients is metastasis to other organs because current therapies do not prevent or eliminate metastatic BC. Here, we show that SM-164, a small molecule inhibitor, which degrades inhibitor of apoptosis proteins (IAPs), eliminated early-stage metastases and reduced progression of advanced BC metastasis from MDA-MB-231 BC cells in bones and lungs of nude mice. Mechanistically, SM-164-induced BC cell death is TNFα-dependent, with TNFα produced by IL-4-polarized macrophages triggering MDA-MB-231 cell apoptosis in combination with SM-164. SM-164 also inhibited expression of RANKL, which mediates interactions between metastatic BC and host microenvironment cells and induces osteoclast-mediated osteolysis. SM-164 did not kill adriamycin-resistant BC cells, while adriamycin inhibited SM-164-resistant BC cell growth, similar to parental cells. We conclude that SM-164 is a promising therapeutic agent for early stage bone and lung metastasis from triple-negative breast cancer that should be given prior to conventional chemotherapy.
乳腺癌（BC）患者面临的最具挑战性的问题是转移到其他器官，因为目前的治疗方法不能预防或消除转移性 BC。在这里，我们表明，小分子抑制剂 SM-164 通过降解凋亡抑制蛋白（IAPs），消除了早期转移，并减少了 MDA-MB-231 BC 细胞在裸鼠骨骼和肺部中的晚期 BC 转移的进展。从机制上讲，SM-164 诱导的 BC 细胞死亡依赖于 TNFα，由 IL-4 极化的巨噬细胞产生的 TNFα与 SM-164 一起触发 MDA-MB-231 细胞凋亡。SM-164 还抑制了 RANKL 的表达，RANKL 介导转移性 BC 与宿主微环境细胞之间的相互作用，并诱导破骨细胞介导的溶骨。SM-164 不会杀死阿霉素耐药的 BC 细胞，而阿霉素抑制了 SM-164 耐药的 BC 细胞生长，与亲本细胞相似。我们得出结论，SM-164 是一种有前途的治疗剂，可用于治疗三阴性乳腺癌的早期骨和肺转移，应在常规化疗之前使用。
