State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, 210009, Nanjing, China.
Cell Death Dis. 2018 Oct 27;9(11):1098. doi: 10.1038/s41419-018-1139-z.
Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22-24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.
沉默 STAT3 已被证实是治疗三阴性乳腺癌（TNBC）的一种很有前途的治疗策略，可解决其预后不良的问题。在这项研究中，天然产物隐丹参酮首先通过基于结构的策略被重塑和修饰为更有效的 STAT3 抑制剂。合成衍生物 KYZ3 在两种 TNBC 细胞系上的抗肿瘤活性比隐丹参酮高 22-24 倍，但对正常乳腺上皮 MCF-10A 细胞几乎没有影响。进一步的研究表明，KYZ3 抑制持续的 STAT3 磷酸化。它还阻止 STAT3 蛋白核易位，以调节包括 Bax 和 Bcl-2 在内的靶癌基因的表达。此外，KYZ3 通过降低 MMP-9 的水平抑制 TNBC 细胞转移，MMP-9 是由激活的 STAT3 直接调节的。STAT3 质粒转染试验表明，KYZ3 主要通过靶向 STAT3 诱导肿瘤细胞凋亡。最后，KYZ3 抑制了 MDA-MB-231 细胞皮下植入体内肿瘤的生长。综上所述，KYZ3 可能是治疗 TNBC 的一种很有前途的癌症治疗剂。
