Triazole/thiadiazole substituted 4′-demethylepipodophyllotoxin derivatives induced apoptosis in HeLa cells by up-regulating TMEM133

• Published in: European journal of pharmacology 2021-08, Vol.905, p.174189, Article 174189
• Main Authors: Zhao, Wei, Duan, Ying, Li, Hong-Mei, Li, Shengying, Shen, Yuemao, Zhang, Youming, Li, Yue-zhong, Tang, Ya-Jie
• Format: Article
• Language: English
• Subjects: 4′-demethylepipodophyllotoxin; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor; Apoptosis - drug effects; Apoptosis - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cell Cycle Checkpoints - drug effects; DNA damage; DNA Damage - drug effects; DNA Repair - drug effects; DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - metabolism; Etoposide - pharmacology; Female; Gene Expression Regulation - drug effects; Gene Knockout Techniques; HeLa Cells; Heterocycles; Histones - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - chemistry; Podophyllotoxin - pharmacology; Thiadiazoles - chemistry; TMEM133 gene; Triazoles - chemistry; Up-Regulation - drug effects
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174189

Heterocycle modification has been widely and successfully employed in the antitumor drugs. However, the different antitumor efficacy was corelated with the heterocycle substituted, and the genetic mechanism underlying these effects has not been elucidated. In this study, the intrinsic regularity between different types of heterocycle-substituted DMEP derivative compounds and the mechanisms of their antitumor activity was preliminarily disclosed. Triazole/thiadiazole substituted 4′-demethylepipodophyllotoxin derivatives induced more severe DNA damage and higher levels of 26S proteasomal Topo IIβ degradation, though inhibited the recruition of γH2AX to resist the DNA damage. The reduced DNA repair led to higher up-regulation of cell cycle arrest proteins, and ultimately DNA damage mediated-ATM/ATR apoptotic pathways and specifically activated DNA damage response gene TMEM133, which induced apoptosis through up-regulation of G2/M cell cycle arrest-related genes. Over-expression and knock-out of TMEM133 demonstrated that TMEM133 is essential for inhibition of the tumor cell growth during treatment with triazole/thiadiazole substituted 4′-demethylepipodophyllotoxin derivatives. [Display omitted]