A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells.
A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells.
复制标题
DOI：
10.1186/1476-4598-9-217
复制
发表时间：
2010-08-16
期刊：
影响因子：
37.3
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Lin L;Deangelis S;Foust E;Fuchs J;Li C;Li PK;Schwartz EB;Lesinski GB;Benson D;Lü J;Hoyt D;Lin J
靶向信号转导子和转录激活子3（STAT 3）信号传导是用于具有组成性激活的STAT 3的大多数类型的人类癌症的有吸引力的治疗方法。FLLL 32是一种新型的小分子STAT 3抑制剂，它是从膳食剂姜黄素中专门设计的，用于抑制多发性骨髓瘤、胶质母细胞瘤、肝癌和结直肠癌细胞中的组成型STAT 3信号传导。FLLL 32被发现是体外STAT 3磷酸化、STAT 3 DNA结合活性和STAT 3下游靶基因表达的有效抑制剂，导致在人多发性骨髓瘤、胶质母细胞瘤、肝癌和结直肠癌细胞系中抑制细胞增殖以及诱导Caspase-3和PARP裂解。然而，使用激酶谱测定，FLLL 32对含有SH 2或SH 2和SH 3结构域的一些酪氨酸激酶以及其他蛋白质和脂质激酶表现出很小的抑制。FLLL 32也比先前报道的四种JAK 2和STAT 3抑制剂以及姜黄素更有效地抑制这些癌细胞中的细胞活力。此外，FLLL 32选择性抑制IL-6诱导的STAT 3磷酸化，但不抑制IFN-γ诱导的STAT 1磷酸化。我们的研究结果表明，FLLL 32对STAT 3表现出有效的抑制活性，并具有靶向表达组成型STAT 3信号传导的多发性骨髓瘤、胶质母细胞瘤、肝癌和结直肠癌细胞的潜力。
Targeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells. FLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-γ. Our findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling.
登录
查看更多内容
影响因子：
4.1
作者：
Rolhion, C;Penault-Llorca, F;Verrelle, P
通讯作者：
Verrelle, P
影响因子：
4.8
作者：
Xiong, Hua;Zhang, Zhi-Gang;Fang, Jing-Yuan
通讯作者：
Fang, Jing-Yuan
影响因子：
8
作者：
Weissenberger, J;Loeffler, S;Weis, J
通讯作者：
Weis, J
影响因子：
6.4
作者：
Chakravarti, Nitin;Myers, Jeffrey N.;Aggarwal, Bharat B.
通讯作者：
Aggarwal, Bharat B.
影响因子：
4.8
作者：
Corvinus, FM;Orth, C;Friedrich, K
通讯作者：
Friedrich, K