A novel 4,6-disubstituted-1,2,4-triazolo-1,3,4-thiadiazole derivative inhibits tumor cell invasion and potentiates the apoptotic effect of TNFα by abrogating NF-κB activation cascade

Apoptosis. 2017 Jan;22(1):145-157. doi: 10.1007/s10495-016-1312-8.

Abstract

Condensed-bicyclic 4,6-substituted1,2,4-triazolo-1,3,4-thiadiazole derivatives (CBTT) have been shown to possess a wide spectrum of pharmacological activities. In this study, several novel CBTT derivatives were synthesized and investigated for their possible role as anti-neoplastic agents. The anti-proliferative effect of various CBTT derivatives was analyzed against tumor cell lines by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay. One of the potential CBTT derivative, 5-(3-(2,3-dichlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)flurobenzonitrile (DTTF) was found to be the most potent against cervical cancer SiHa cells and exhibited minimal effect against normal cells. Molecular docking analysis indicated that transcription factor NF-κB was one of the potential molecular targets modulated by DTTF. Specifically, the drug blocked the TNFα-induced phosphorylation of upstream IκBα kinase in a time-dependent manner leading to the suppression of NF-κB activation and nuclear translocation. DTTF also potentiated the apoptotic effect of TNFα, as well as significantly inhibited migration and invasion of tumor cells. Overall, these findings indicate a potential novel role and mechanism(s) of action of DTTF as an anticancer agent against diverse malignancies.

Keywords: Apoptosis; Invasion; NF-kB; TNFa; Thiadiazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Female
  • Humans
  • I-kappa B Kinase / chemistry
  • I-kappa B Kinase / genetics*
  • Molecular Docking Simulation
  • NF-kappa B / chemistry
  • NF-kappa B / genetics
  • Neoplasm Invasiveness / genetics
  • Phosphorylation
  • Signal Transduction / drug effects
  • Thiadiazoles / administration & dosage
  • Thiadiazoles / chemistry
  • Transcription Factor RelA / chemistry
  • Transcription Factor RelA / genetics
  • Tumor Necrosis Factor-alpha / genetics*
  • Uterine Cervical Neoplasms / drug therapy*
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / pathology

Substances

  • NF-kappa B
  • RELA protein, human
  • TNF protein, human
  • Thiadiazoles
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • 1,3,4-thiadiazole
  • I-kappa B Kinase