HJC0152 suppresses human non-small-cell lung cancer by inhibiting STAT3 and modulating metabolism.

OBJECTIVES

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non-small-cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC.

MATERIALS AND METHODS

We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC-QTOF/MS was used for untargeted metabolomic relative quantitation analysis.

RESULTS

We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways.

CONCLUSIONS

HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti-cancer effects.