Small-molecule targeting of signal transducer and activator of transcription (STAT) 3 to treat non-small cell lung cancer

Abstract

Objective Lung cancer is the leading cause of cancer death in both men and women. Non-small cell lung cancer (NSCLC) has an overall 5-year survival rate of 15%. While aberrant STAT3 activation has previously been observed in NSCLC, the scope of its contribution is uncertain and agents that target STAT3 for treatment are not available clinically. Methods We determined levels of activated STAT3 (STAT3 phosphorylated on Y705, pSTAT3) and the two major isoforms of STAT3 (α and β) in protein extracts of 8 NSCLC cell lines, as well as the effects of targeting STAT3 in vitro and in vivo in NSCLC cells using short hairpin (sh) RNA and two novel small-molecule STAT3 inhibitors, C188-9 and piperlongumine (PL). Results Levels of pSTAT3, STAT3α, and STATβ were increased in 7 of 8 NSCLC cell lines. Of note, levels of pSTAT3 were tightly correlated with levels of STAT3β, but not STAT3α. Targeting of STAT3 in A549 cells using shRNA decreased tSTAT3 by 75%; this was accompanied by a 47–78% reduction in anchorage-dependent and anchorage-independent growth and a 28–45% reduction in mRNA levels for anti-apoptotic STAT3 gene targets. C188-9 and PL (@30μM) each reduced pSTAT3 levels in all NSCLC cell lines tested by ≥50%, reduced anti-apoptotic protein mRNA levels by 25–60%, and reduced both anchorage-dependent and anchorage-independent growth of NSCLC cell lines with IC50 values ranging from 3.06–52.44μM and 0.86–11.66μM, respectively. Treatment of nude mice bearing A549 tumor xenografts with C188-9 or PL blocked tumor growth and reduced levels of pSTAT3 and mRNA encoding anti-apoptotic proteins. Conclusion STAT3 is essential for growth of NSCLC cell lines and tumors and its targeting using C188-9 or PL may be a useful strategy for treatment.

STAT3 inhibitor enhances chemotherapy drug efficacy by modulating mucin 1 expression in non-small cell lung carcinoma

“…Our results showed an association of combined elevated expression of STAT3 and MUC1 in cancer patient samples with poor chemotherapy response (median overall Our results demonstrated that STAT3 protein is constitutively over-expressed in NSCLC, and could contribute to the regulation of MUC1 mRNA and protein levels. Earlier reports have also indicated the cross-talk of these proteins and have implicated for their functions to promote tumor cell survival [17]. However, the results from -STAT3 and MUC1 knockdown experiments it is evident that -that STAT3 acts at the upstream signaling level and regulate the MUC1 expression.…”

“…Multiple studies have shown that STAT proteins particularly, STAT3 is abnormally activated in a wide variety of cancer type including NSCLC, and targeting them could provide therapeutic options [12][13][14][15][16][17]. Similarly, MUC1 protein, which is modulated by STAT3 levels, is also indicated to facilitate for tumor survival and progression [18,19].…”

Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice

“…C188-9 binds to the SH2 domain of STAT3 and blocks its recruitment to the kinase-containing receptor complexes, its tyrosine phosphorylation, and its homodimerization. STAT3 activation can lead to tumorigenesis in diverse type of cancers (18-21). We demonstrated that C188-9 had beneficial effects on both hepatic tumor and NASH in liver, with blockage of tumor growth and progression, prevention of tumor development, reduction of steatosis, inflammation and hepatocellular ballooning, resulting in NASH reversion, and reduction of bile ductular reaction and associated fibrosis.…”

“…In a drug development program involving virtual ligand screening, 2-D similarity screening, 3-D pharmacophore analysis, and SAR-based medicinal chemistry, we identified C188-9 as a potent small-molecule that targets the Src-homology (SH) 2 domain of STAT3 (18-21). C188-9 inhibited growth and survival of several cancer cell lines in vitro , including breast cancer (18), acute myeloid leukemia (19), head and neck squamous cell carcinoma (20) and non-small cell lung cancer (21).…”

“…C188-9 inhibited growth and survival of several cancer cell lines in vitro , including breast cancer (18), acute myeloid leukemia (19), head and neck squamous cell carcinoma (20) and non-small cell lung cancer (21). To test the effects of C188-9 on HCC and underlying liver disease, we herein used mice with hepatocyte-specific deletion of Pten (Hep Pten - mice).…”