Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR­mutated NSCLC cells in vitro and in vivo via STAT3/Bcl­2 signaling.

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used in the treatment of non­small cell lung cancer (NSCLC). However, erlotinib resistance leads to high mortality in patients with NSCLC, while the activation of STAT3 is closely related to erlotinib resistance. Studies have shown that the main components of Huanglian Jiedu Decoction (HJD) have antitumor effects. Therefore, the anticancer effect of HJD combined with erlotinib on NSCLC cells was investigated. The NSCLC HCC827, HCC827ER, and H1975 cell lines as well as xenograft nude mice were selected as models to study the effects of HJD. The proapoptotic effects of HJD were examined by CCK­8 and apoptosis assays. ELISA, immunostaining, and western blot analysis were also performed. HJD considerably enhanced the anticancer effect of erlotinib in both EGFR­TKI­resistant and ­sensitive NSCLC cells. HJD promoted erlotinib­induced apoptosis and caspase 3 activity. The co­treatment also inhibited the expression of Bcl­XL, Bcl­2, and p­STAT3. In addition, siSTAT3 had similar functions with HJD. In particular, the apoptotic rates of erlotinib­stimulated HCC827, HCC827ER, and H1975 cells were enhanced by transfecting siSTAT3. Furthermore, overexpression of STAT3 significantly inhibited HJD­mediated erlotinib sensitization. The combined use of HJD with erlotinib significantly reduced tumor growth in erlotinib­resistant HCC827ER and H1975 xenografts, induced caspase 3, and inhibited Ki67, STAT3, and Bcl­2 expression. HJD significantly alleviated erlotinib resistance by regulating the STAT3/Bcl­2 signaling pathway, which is a promising method to overcome the EGFR­TKI resistance of NSCLC.