Effect of Diacerein on HOTAIR/IL-6/STAT3, Wnt/β-Catenin and TLR-4/NF-κB/TNF-α axes in colon carcinogenesis

Environ Toxicol Pharmacol. 2022 Oct:95:103943. doi: 10.1016/j.etap.2022.103943. Epub 2022 Aug 5.

Abstract

Colorectal cancer (CRC) is a common malignancy with high mortality and poor prognosis. Diacerein (DIA) is an anti-inflammatory used for treatment of osteoarthritis. We delineated some underlying molecular mechanisms of DIA's anti-carcinogenic effect in CRC using in vivo and in vitro models. Human Caco-2 cells were treated with DIA followed by MTT and Annexin V assays and CRC was experimentally induced using 1,2-dimethylhydrazine. DIA (50 mg/kg/day, orally) was administrated for 8 weeks. The MTT assay confirmed cytotoxic effect of DIA in vitro and Annexin V confirmed its apoptotic effect. DIA resulted in regression of tumour lesions with reduced colonic TLR4, NF-κB and TNF-α protein levels and down-regulated VEGF expression, confirming anti-angiogenic impact. DIA triggered caspase-3 expression and regulated Wnt/β-Catenin pathway, by apparently interrupting the IL-6/STAT3/ lncRNA HOTAIR axis. In conclusion, DIA disrupted IL-6/STAT3/ lncRNA HOTAIR axis which could offer an effective therapeutic strategy for the management of CRC.

Keywords: Apoptosis; Colorectal cancer; Diacerein; IL-6/STAT3/ lncRNA HOTAIR; Inflammation.

MeSH terms

  • 1,2-Dimethylhydrazine / metabolism
  • 1,2-Dimethylhydrazine / pharmacology
  • Annexin A5
  • Anthraquinones
  • Anti-Inflammatory Agents / pharmacology
  • Anticarcinogenic Agents* / pharmacology
  • Caco-2 Cells
  • Carcinogenesis / metabolism
  • Caspase 3 / metabolism
  • Cell Proliferation
  • Colon
  • Humans
  • Interleukin-6 / metabolism
  • NF-kappa B / metabolism
  • RNA, Long Noncoding* / genetics
  • STAT3 Transcription Factor
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • Wnt Signaling Pathway
  • beta Catenin / metabolism

Substances

  • Annexin A5
  • Anthraquinones
  • Anti-Inflammatory Agents
  • Anticarcinogenic Agents
  • Interleukin-6
  • NF-kappa B
  • RNA, Long Noncoding
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • beta Catenin
  • diacerein
  • Caspase 3
  • 1,2-Dimethylhydrazine