Novel STAT3 Phosphorylation Inhibitors Exhibit Potent Growth-Suppressive Activity in Pancreatic and Breast Cancer Cells

Abstract

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 IFNα 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. Cancer Res; 70(6); 2445-54. ©2010 AACR.

IL-6, a risk factor for hepatocellular carcinoma: FLLL32 inhibits IL-6-Induced STAT3 phosphorylation in human hepatocellular cancer cells

“…20 FLLL32 is a curcumin analog, the modification of which can better interact with binding sites of JAK2 and dimerization domain of STAT3. The treatment of FLLL32 can suppress JAK2 activity 18 but did not affect JAK2 expression or phosphorylation (Fig. 4B).…”

“…FLLL32 is a new curcumin analog designed in our laboratory, which can specifically inhibit STAT3 in vitro and in vivo. 18 We concluded that, compared to anti-IL-6 antibody, STAT3 small-molecule inhibitors can block IL-6-induced STAT3 activation much more effectively.…”

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“…This pro-inflammatory cytokine is implicated in a milieu of cancer types because of its propensity to drive the activation of the oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3). By virtue of interacting with other transcription factors (e.g., NF-B), STAT3 is known to mediate crosstalk between tumor cells and inflammatory cells within the tumor microenvironment and promote the development and progression of multiple types of human cancers [12][13][14][15][16][17]. The expression of STAT3 and presence of its active form (i.e., phosphorylated form) is increased in tumor tissues from patients and this pronounced expression indicates a poor prognosis in a variety of cancers [18].…”

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

“…Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-androgenic activity of 4-ethoxycarbonylethylenyl curcumin. Di-tetrapyranylated-4-ethoxycarbonylethylenyl curcumin (85), which exists only in the keto-enol form, has potent anti-androgenic activity, which may be a good lead compound for further structural modifications. Based on the SAR information, five new compounds were designed and subsequently synthesized.…”

“…The compounds 101-105 were found to induce cytotoxicity against B16 melanoma cells, while compound 102 was found to inhibit tubulin polymerization. Lin et al [85] have developed signal transducer and activator of transcription-3 (STAT3) inhibitors, known as FLLL31 (106) and FLLL32 (107), which are derived by functionalization of the methylenic position in curcumin. These compounds are designed to bind selectively to Janus kinase-2 and the STAT3 Src homology-2 domain, which serve crucial role in STAT3 dimerization and signal transduction.…”