p38 inhibitor inhibits the apoptosis of cowanin-treated human colorectal adenocarcinoma cells

Int J Oncol. 2018 Jun;52(6):2031-2040. doi: 10.3892/ijo.2018.4353. Epub 2018 Apr 3.

Abstract

Colorectal cancer, which is the third most common type of cancer diagnosed in both men and women, is the leading cause of cancer-related deaths worldwide. Cowanin is a pure compound extracted from Garcinia cowa Roxb., a tree species present in Thailand, Malaysia and Myanmar. The crude extract has been demonstrated to have antitumor activity, inflammation induction, antibacterial activity, anti-inflammatory activity and antimalarial activity. In the present study, the effects of cowanin on apoptosis induction and on the apoptosis-related and mitogen-activated protein kinase (MAPK) pathways were investigated in the LoVo human colorectal cancer cell line. The cytotoxicity of cowanin in LoVo cells was determined by MTT assay. Hoechst 33342 and JC‑1 staining were used to determine nuclear morphological changes and mitochondrial membrane potential, respectively. The expression levels of BCL2 apoptosis regulator (Bcl‑2) family, MAPK and AKT serine/threonine kinase 1 (Akt) pathway proteins following cowanin treatment were determined by western blot analysis. The results demonstrated that cowanin inhibited cell proliferation and induced cell death via the apoptosis pathway. Cowanin treatment increased BCL2 associated X (Bax) and decreased Bcl‑2 expression. In addition, cowanin activated caspase‑9, -7 and poly-ADP-ribose-polymerase expression. Furthermore, cowanin decreased the levels of phosphorylated extracellular signal-regulated kinase (p‑ERK), p‑Akt, p‑3‑phosphoinositide‑dependent protein kinase‑1, while it increased p‑p38 expression, thus resulting in the induction of apoptosis. In conclusion, cowanin inhibited cell proliferation and induced apoptosis of LoVo cells via the MAPK and Akt signaling pathways. Notably, inhibition of p38 by using a p38 inhibitor (SB203580) prevented the cowanin-induced apoptosis in LoVo cells. These results suggested that cowanin may be a potential candidate for the treatment of colorectal cancer and provided important information on the molecular mechanisms underlying its antitumor activity.

MeSH terms

  • Caspase 7 / metabolism
  • Caspase 9 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridines / pharmacology*
  • Tannins / chemistry
  • Tannins / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Imidazoles
  • Pyridines
  • Tannins
  • cowaniin
  • Poly(ADP-ribose) Polymerases
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases
  • CASP7 protein, human
  • CASP9 protein, human
  • Caspase 7
  • Caspase 9
  • SB 203580