Abstract
The Janus kinase-2 (Jak2)-signal transducer and activator of transcription-3 (STAT3) pathway is critical for promoting an oncogenic and metastatic phenotype in several types of cancer including renal cell carcinoma (RCC) and melanoma. This study describes two small molecule inhibitors of the Jak2-STAT3 pathway, FLLL32 and its more soluble analog, FLLL62. These compounds are structurally distinct curcumin analogs that bind selectively to the SH2 domain of STAT3 to inhibit its phosphorylation and dimerization. We hypothesized that FLLL32 and FLLL62 would induce apoptosis in RCC and melanoma cells and display specificity for the Jak2-STAT3 pathway. FLLL32 and FLLL62 could inhibit STAT3 dimerization in vitro. These compounds reduced basal STAT3 phosphorylation (pSTAT3), and induced apoptosis in four separate human RCC cell lines and in human melanoma cell lines as determined by Annexin V/PI staining. Apoptosis was also confirmed by immunoblot analysis of caspase-3 processing and PARP cleavage. Pre-treatment of RCC and melanoma cell lines with FLLL32/62 did not inhibit IFN-γ-induced pSTAT1. In contrast to FLLL32, curcumin and FLLL62 reduced downstream STAT1-mediated gene expression of IRF1 as determined by Real Time PCR. FLLL32 and FLLL62 significantly reduced secretion of VEGF from RCC cell lines in a dose-dependent manner as determined by ELISA. Finally, each of these compounds inhibited in vitro generation of myeloid-derived suppressor cells. These data support further investigation of FLLL32 and FLLL62 as lead compounds for STAT3 inhibition in RCC and melanoma.
Highlights
Renal cell carcinoma (RCC) represents an increasing cause of cancer morbidity and mortality worldwide
Structure-activity relationship studies using a docking approach indicate that FLLL32 and FLLL62 bind to the signal transducer and activator of transcription-3 (STAT3) SH2 domain almost identically (Figure 1B)
In the present study we demonstrate that the structure of a novel curcumin analog, FLLL32 can be modified to improve its solubility profile without compromising much of its functional activity or specificity
Summary
Renal cell carcinoma (RCC) represents an increasing cause of cancer morbidity and mortality worldwide. Recent trials have demonstrated that agents designed to target these pathways, including sorafenib, sunitinib, bevacizumab, everolimus, temsirolimus and pazopanib prolong progression free survival. These studies have led to the approval of these agents for treatment of metastatic RCC by the FDA and EMA [10,11]. These data highlight the potential for targeted therapy in the management of RCC, and set the precedent for novel combination therapies, as drug resistance remains a legitimate concern for this disease
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