Department of Pediatrics, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43205, USA.
Cancer Res. 2010 Mar 15;70(6):2445-54. doi: 10.1158/0008-5472.CAN-09-2468. Epub 2010 Mar 9.
The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small-molecule STAT3 inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNalpha and interleukin-6 in breast cancer cells. We also show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling.
信号转导子和转录激活子 3（STAT3）的组成性激活在大多数类型的人类癌症中经常被检测到，在这些癌症中，它在生存、耐药性、血管生成和其他功能中发挥着重要作用。因此，针对组成性 STAT3 信号是这些癌症的一种有吸引力的治疗方法。我们最近开发了新型小分子 STAT3 抑制剂，称为 FLLL31 和 FLLL32，它们源自姜黄素（姜黄的主要生物活性化合物）。这些化合物旨在选择性地与 Janus 激酶 2 和 STAT3 Src 同源-2 结构域结合，这在 STAT3 二聚化和信号转导中起着至关重要的作用。在这里，我们表明 FLLL31 和 FLLL32 是体外 STAT3 磷酸化、DNA 结合活性和转录激活的有效抑制剂，导致多种致癌过程受阻，并诱导胰腺和乳腺癌细胞系凋亡。FLLL31 和 FLLL32 还抑制软琼脂中的集落形成、细胞侵袭，并与抗癌药物阿霉素对乳腺癌细胞表现出协同作用。此外，我们表明 FLLL32 可以抑制 IFNalpha 和白细胞介素-6 在乳腺癌细胞中诱导的 STAT3 磷酸化。我们还表明，FLLL32 的给药可以抑制鸡胚异种移植物中的肿瘤生长和血管生成，并大大减少小鼠异种移植物中的肿瘤体积。我们的研究结果强调了这些新化合物的潜力及其针对表现出组成性 STAT3 信号的胰腺和乳腺癌的疗效。
