Tizoxanide Promotes Apoptosis in Glioblastoma by Inhibiting CDK1 Activity

Si Huang; Jingxian Xiao; Junyong Wu; Jiayi Liu; Xueping Feng; Chengdong Yang; Daxiong Xiang; Shilin Luo

doi:10.3389/fphar.2022.895573

Tizoxanide Promotes Apoptosis in Glioblastoma by Inhibiting CDK1 Activity

Front Pharmacol. 2022 May 25:13:895573. doi: 10.3389/fphar.2022.895573. eCollection 2022.

Authors

Si Huang^{1

2}, Jingxian Xiao³, Junyong Wu^{1

2}, Jiayi Liu⁴, Xueping Feng⁵, Chengdong Yang⁶, Daxiong Xiang^{1

2}, Shilin Luo^{1

2}

Affiliations

¹ Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.
² Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China.
³ School of Medical Science, Hunan University of Medicine, Huaihua, China.
⁴ Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China.
⁵ Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, China.
⁶ Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.

Abstract

The antiparasitic drug nitazoxanide (NTZ) has received considerable attention for its potential in cancer therapy. In this study, we demonstrate that tizoxanide (TIZ), an active metabolite of NTZ, exhibits antiglioma activity in vitro and in vivo by inducing G2/M cell cycle arrest and apoptosis. In vitro, TIZ dose-dependently inhibited the proliferation of U87, U118, and A172 human glioblastoma (GBM) cells at 48 h with IC₅₀ values of 1.10, 2.31, and 0.73 µM, respectively. Treatment with TIZ (1 and 10 µM) also dose-dependently inhibited the colony formation of these GBM cells and accumulated ROS damage in the nucleus. In silico target fishing combined with network pharmacological disease spectrum analyses of GBM revealed that cycle-dependent kinase 1 (CDK1) is the most compatible target for TIZ and molecular docking by Molecule Operating Environment (MOE) software confirmed it. Mechanistically, TIZ inhibited the phosphorylation of CDK1 at Thr161 and decreased the activity of the CDK1/cyclin B1 complex, arresting the cell cycle at the G2/M phase. TIZ may induce apoptosis via the ROS-mediated apoptotic pathway. In vivo, TIZ suppressed the growth of established subcutaneous and intracranial orthotopic xenograft models of GBM without causing obvious side effects and prolonged the survival of nude mice bearing glioma. Taken together, our results demonstrated that TIZ might be a promising chemotherapy drug in the treatment of GBM.

Keywords: Cdk1; apoptosis; cell cycle; glioblastoma; tizoxanide.