Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer

Zhipan Liang; Qiuyun Chen; Liuying Pan; Xiaowei She; Tengfei Chen

doi:10.21037/jtd-23-1978

Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer

J Thorac Dis. 2024 Feb 29;16(2):1412-1423. doi: 10.21037/jtd-23-1978. Epub 2024 Feb 27.

Authors

Zhipan Liang^#¹, Qiuyun Chen^#², Liuying Pan¹, Xiaowei She¹, Tengfei Chen¹

Affiliations

¹ Department of Thoracic Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
² Department of Clinical Nursing, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, China.

^# Contributed equally.

Abstract

Background: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell.

Methods: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth.

Results: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo.

Conclusions: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.

Keywords: Non-small cell lung cancer (NSCLC); mebendazole (MBZ); reactive oxygen species (ROS); signal transducer and activator of the transcription 3 (STAT3).