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A silyl andrographolide analogue suppresses Wnt/β-catenin signaling pathway in colon cancer

Somrudee Reabroi1, Arthit Chairoungdua2, Rungnapha Saeeng3

  • 1Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|March 5, 2018
PubMed

Insights

Andrographolide analogue 3A.1 effectively inhibits colorectal cancer (CRC) cell growth by targeting the Wnt/β-catenin/GSK-3β pathway. This compound shows therapeutic potential for CRC treatment by inducing apoptosis and DNA damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hyperactivation of Wnt/β-catenin signaling is a key driver in colorectal cancer (CRC) oncogenesis.
  • Andrographolide analogue 3A.1 exhibits potent cytotoxicity against cancer cells via unknown mechanisms.
  • Colon cancer HT29 cells demonstrate higher sensitivity to analogue 3A.1 compared to HCT116 and SW480 cells.

Purpose of the Study:

  • To investigate the anti-cancer activity of andrographolide analogue 3A.1 on Wnt/β-catenin signaling in HT29 colon cancer cells.
  • To elucidate the molecular mechanisms underlying the cytotoxic effects of analogue 3A.1.
  • To evaluate the therapeutic potential of analogue 3A.1 in colorectal cancer treatment.

Main Methods:

  • Assessing cell viability and proliferation using IC50 values and dose-dependent assays.
  • Analyzing apoptosis induction and DNA damage markers (PARP-1, γ-H2AX).
  • Measuring T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter activity and Wnt target gene/β-catenin expression.
  • Evaluating the role of GSK-3β kinase activity and using GSK-3β inhibitor and mutant β-catenin.

Main Results:

  • Analogue 3A.1 significantly inhibited HT29 cell viability (IC50: 11.1 ± 1.4 μM at 24h) and proliferation, inducing apoptosis.
  • Apoptosis was associated with increased DNA damage markers PARP-1 and γ-H2AX.
  • Analogue 3A.1 suppressed Wnt/β-catenin signaling by inhibiting TCF/LEF promoter activity, downregulating Wnt target genes and β-catenin protein.
  • Increased GSK-3β kinase activity was observed, with effects blocked by GSK-3β inhibitor and mutant β-catenin.

Conclusions:

  • Analogue 3A.1 exerts anti-cancer effects by inhibiting the Wnt/β-catenin/GSK-3β pathway in colon cancer cells.
  • The compound induces DNA damage and apoptosis, contributing to its cytotoxic activity.
  • Andrographolide analogue 3A.1 demonstrates significant therapeutic potential for colorectal cancer treatment.
Keywords:
Andrographolide analogueAnti-cancerColorectal cancerGSK-3βWnt/β-catenin

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