Han Kunkun, Xu Xin, Xu Zhuan, Chen Guodong, Zeng Yuanying, Zhang Zubin, Cao Biyin, Kong Yan, Tang Xiaowen, Mao Xinliang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Sci Rep. 2015 Sep 2;5:12809. doi: 10.1038/srep12809.
The mammalian target of rapamycin (mTOR) is extensively involved in multiple myeloma (MM) pathophysiology. In the present study, we reported a novel small molecule SC06 that induced MM cell apoptosis and delayed MM xenograft growth in vivo. Oral administration of SC06 to mice bearing human MM xenografts resulted in significant inhibition of tumor growth at doses that were well tolerated. Mechanistic studies revealed that SC06 selectively inhibited the mTOR signaling pathway but had no effects on other associated kinases, such as AKT, ERK, p38, c-Src and JNK. Further studies showed that SC06-decreased mTOR activation was associated with the downregulation of Raptor, a key component of the mTORC1 complex. SC06 also suppressed the phosphorylation of 4E-BP1 and P70S6K, two typical substrates in the mTORC1 signaling pathway. Notably, expression of Raptor, phosphorylation of mTOR and phosphorylated 4E-BP1 was also decreased in the tumor tissues from SC06-treated mice, which was consistent with the cellular studies. Therefore, given the potency and low toxicity, SC06 could be developed as a potential anti-MM drug candidate by disrupting the mTOR signaling.
雷帕霉素的哺乳动物靶点（mTOR）广泛参与多发性骨髓瘤（MM）的病理生理过程。在本研究中，我们报道了一种新型小分子SC06，它可诱导MM细胞凋亡并延缓MM异种移植瘤在体内的生长。给携带人MM异种移植瘤的小鼠口服SC06，在耐受性良好的剂量下可显著抑制肿瘤生长。机制研究表明，SC06选择性抑制mTOR信号通路，但对其他相关激酶如AKT、ERK、p38、c-Src和JNK没有影响。进一步研究表明，SC06降低mTOR激活与mTORC1复合物的关键组分Raptor的下调有关。SC06还抑制了mTORC1信号通路中的两个典型底物4E-BP1和P70S6K的磷酸化。值得注意的是，在SC06处理小鼠的肿瘤组织中，Raptor的表达、mTOR的磷酸化以及磷酸化4E-BP1也降低，这与细胞研究结果一致。因此，鉴于其有效性和低毒性，SC06有望通过破坏mTOR信号通路而被开发成为一种潜在的抗MM药物候选物。
