Flubendazole Elicits Antitumor Effects by Inhibiting STAT3 and Activating Autophagy in Non-small Cell Lung Cancer.

Xiaona Xie,Haiyang Zhao,Feng Zhou,Lehe Yang,Chunhui Jiang,Yemeng Tang,Liangxing Wang,Xiaoying Huang,Zhiguo Liu,Chengguang Zhao,Xueding Cai

doi:10.3389/fcell.2021.680600

Abstract

Non-small cell lung carcinoma (NSCLC) is a major neoplastic disease with a high mortality worldwide; however, effective treatment of this disease remains a challenge. Flubendazole, a traditional anthelmintic drug, possesses potent antitumor properties; however, the detailed molecular mechanism of flubendazole activity in NSCLC needs to be further explored. In the present study, flubendazole was found to exhibit valid antitumor activity in vitro as well as in vivo. Flubendazole blocked phosphorylation of STAT3 in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptotic proteins. Further, flubendazole inhibited STAT3 activation by inhibiting its phosphorylation and nuclear localization induced by interleukin-6 (IL-6). Notably, the autophagic flux of NSCLC cell lines was increased after flubendazole treatment. Furthermore, flubendazole downregulated the expression of BCL2, P62, and phosphorylated-mTOR, but it upregulated LC3-I/II and Beclin-1 expression, which are the main genes associated with autophagy. Collectively, these data contribute to elucidating the efficacy of flubendazole as an anticancer drug, demonstrating its potential as a therapeutic agent via its suppression of STAT3 activity and the activation of autophagy in NSCLC.

Highlights

Non-small cell lung carcinoma (NSCLC) refers to the widest variety of carcinomas and primarily causes carcinoma-associated deaths globally, as suggested by the latest annual report on global carcinoma statistics (Hua et al, 2020)
The inhibitory effects exerted by flubendazole in normal human cells BEAS-2b and human umbilical vein endothelial cells (HUVEC) were significantly less compared to those exerted on carcinoma cells under the same exposure time, with an IC50 value at 48 h that is greater than 100 μM (Figure 1D)
These data suggested that flubendazole effectively restricted the viability of NSCLC cells and that exposure to it was safe for normal cells

Summary

Introduction

Non-small cell lung carcinoma (NSCLC) refers to the widest variety of carcinomas and primarily causes carcinoma-associated deaths globally, as suggested by the latest annual report on global carcinoma statistics (Hua et al, 2020). The mechanisms underlying NSCLC development need to be identified to develop new and highly efficient therapies targeting the molecular level. STAT3 is constitutively active in various carcinomas, including colon, prostate, breast, and lung carcinomas (Mora et al, 2002; Banerjee and Resat, 2016; Huynh et al, 2019; Lin et al, 2019; Wei et al, 2019; Yang et al, 2020; Zhao et al, 2020). Inhibiting STAT3 activation represents a targeted therapeutic strategy to treat carcinomas (Huynh et al, 2019; Wei et al, 2019). The development of STAT3 inhibitors continues to be an active area of research, since no other effective inhibitory agents have been approved for treating NSCLC

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