Structurally modified curcumin analogs inhibit STAT3 phosphorylation and promote apoptosis of human renal cell carcinoma and melanoma cell lines

• Published in: PloS one Vol. 7; no. 8; p. e40724
• Main Authors: Bill, Matthew A, Nicholas, Courtney, Mace, Thomas A, Etter, Jonathan P, Li, Chenglong, Schwartz, Eric B, Fuchs, James R, Young, Gregory S, Lin, Li, Lin, Jiayuh, He, Lei, Phelps, Mitch, Li, Pui-Kai, Lesinski, Gregory B
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10-08-2012; Public Library of Science (PLoS)
• Subjects: Analogs; Analysis; Angiogenesis; Annexin V; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biology; Biotechnology; Cancer prevention; Cancer therapies; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Caspase; Caspase-3; Cell growth; Cell Line, Tumor; Clear cell-type renal cell carcinoma; Curcumin; Curcumin - analogs & derivatives; Curcumin - chemistry; Curcumin - pharmacology; Dimerization; Enzyme-linked immunosorbent assay; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Hospitals; Humans; Inhibition; Interferon regulatory factor 1; Interferon-gamma - pharmacology; Internal medicine; Janus kinase; Janus kinase 2; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Kidney cancer; Lead compounds; Leukocytes, Mononuclear - cytology; Leukocytes, Mononuclear - drug effects; Medical prognosis; Medicine; Melanoma; Melanoma - genetics; Melanoma - metabolism; Metastases; Metastasis; Molecular Docking Simulation; Pediatrics; Pharmaceutical sciences; Pharmacy; Phenotypes; Phosphorylation; Phosphorylation - drug effects; Poly(ADP-ribose) polymerase; Pretreatment; Protein Multimerization - drug effects; Pyrans - chemistry; Pyrans - pharmacology; Renal cell carcinoma; Signal Transduction - drug effects; Skin cancer; Solubility; Stat1 protein; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - chemistry; STAT3 Transcription Factor - metabolism; Suppressor cells; Transcription; Tumor cell lines; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis; γ-Interferon; Cleveland Ohio; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040724

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.