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Evaluation of Novel 3-Hydroxyflavone Analogues as HDAC Inhibitors against Colorectal Cancer

Subhankar Biswas1, Neetinkumar D Reddy1, B S Jayashree2

  • 1Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.

Advances in Pharmacological Sciences
|January 29, 2019
PubMed

Insights

Novel 3-hydroxyflavone analogues show promise as histone deacetylase 8 (HDAC8) inhibitors for colon cancer treatment. These compounds effectively inhibited HDAC8, induced cancer cell apoptosis, and reduced tumor growth in vivo.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase 8 (HDAC8) is overexpressed in colon cancer, making it a therapeutic target.
  • Flavonols, like quercetin, show anticancer potential but have limited clinical use.
  • Developing novel HDAC8 inhibitors is crucial for effective colon cancer therapy.

Purpose of the Study:

  • To synthesize and evaluate novel 3-hydroxyflavone analogues as potential HDAC8 inhibitors.
  • To assess the anticancer properties of these analogues against colorectal cancer.
  • To investigate their mechanism of action, including apoptosis induction and in vivo efficacy.

Main Methods:

  • Synthesis of 3-hydroxyflavone analogues.
  • Cytotoxicity assessment using MTT assay.
  • HDAC enzyme inhibition assays (nonspecific and specific).
  • Apoptosis induction studies (Annexin V, caspase 3/7 assay).
  • In vivo colorectal cancer models.

Main Results:

  • Two analogues, QMJ-2 and QMJ-5, exhibited significant cytotoxicity against HCT116 cells.
  • QMJ-5 demonstrated specific inhibition of HDAC8.
  • Analogues reduced HDAC8 expression and increased acetyl H3K9 levels.
  • Both analogues induced apoptosis and reduced tumor growth in vivo.
  • Aberrant crypt foci formation was decreased in treatment groups.

Conclusions:

  • Novel 3-hydroxyflavone analogues, particularly QMJ-5, are potent HDAC8 inhibitors.
  • These compounds possess significant anticancer properties against colorectal cancer.
  • The findings support the development of these analogues as therapeutic agents for colon cancer.

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