Ketchart Wannarasmi, Yeh I-Ju, Zhou Haoyan, Thiagarajan Praveena S, Lathia Justin, Reizes Ofer, Exner Agata, Su Bin, Montano Monica M
Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA; Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Cancer Lett. 2016 Aug 28;379(1):60-9. doi: 10.1016/j.canlet.2016.05.029. Epub 2016 May 26.
We have been studying the role of Hexamethylene bisacetamide (HMBA) Induced Protein 1 (HEXIM1) as a tumor suppressor whose expression is decreased in tamoxifen resistant and metastatic breast cancer. HMBA was considered the most potent and specific inducer for HMBA inducible protein 1 (HEXIM1) prior to our studies. Moreover, the ability of HMBA to induce differentiation is advantageous for its therapeutic use when compared to cytotoxic agents. However, HMBA induced HEXIM1 expression required at mM concentrations and induced dose limiting toxicity, thrombocytopenia. Thus we structurally optimized HMBA and identified a more potent inducer of HEXIM1 expression, 4a1. The studies reported herein tested the ability of 4a1 to induce HEXIM1 activities using a combination of biochemical, cell phenotypic, and in vivo assays. 4a1 induced breast cell differentiation, including the stem cell fraction in triple negative breast cancer cells. Clinically relevant HEXIM1 activities that are also induced by 4a1 include enhancement of the inhibitory effects of tamoxifen and inhibition of breast tumor metastasis. We also provide mechanistic basis for the phenotypic effects of 4a1. Our results support the potential of an unsymmetrical HMBA derivative, such as 4a1, as lead compound for further drug development.
我们一直在研究六亚甲基双乙酰胺（HMBA）诱导蛋白1（HEXIM1）作为一种肿瘤抑制因子的作用，其在抗他莫昔芬和转移性乳腺癌中的表达会降低。在我们的研究之前，HMBA被认为是HMBA诱导蛋白1（HEXIM1）最有效和最特异的诱导剂。此外，与细胞毒性药物相比，HMBA诱导分化的能力对其治疗应用具有优势。然而，HMBA诱导HEXIM1表达需要毫摩尔浓度，并且会诱导剂量限制性毒性，即血小板减少症。因此，我们对HMBA进行了结构优化，鉴定出一种更有效的HEXIM1表达诱导剂4a1。本文报道的研究使用生化、细胞表型和体内试验相结合的方法，测试了4a1诱导HEXIM1活性的能力。4a1诱导乳腺细胞分化，包括三阴性乳腺癌细胞中的干细胞部分。4a1还诱导的临床相关HEXIM1活性包括增强他莫昔芬的抑制作用和抑制乳腺肿瘤转移。我们还为4a1的表型效应提供了机制基础。我们的结果支持了一种不对称HMBA衍生物，如4a1，作为进一步药物开发先导化合物的潜力。
