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Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells

Marta Di Martile1, Marianna Desideri1, Teresa De Luca1

  • 1Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.

Oncotarget
|February 13, 2016
PubMed

Insights

The novel compound CPTH6 effectively targets lung cancer stem-like cells (LCSCs) by inhibiting histone acetyltransferase (HAT), leading to apoptosis and reduced tumor growth. This suggests HAT inhibition is a promising strategy for non-small cell lung cancer (NSCLC) therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance in various cancers, including non-small cell lung cancer (NSCLC).
  • Targeting CSCs is crucial for developing more effective cancer therapies to prevent relapse and treatment failure.

Purpose of the Study:

  • To evaluate the efficacy of a novel thiazole derivative, CPTH6, as a small molecule inhibitor targeting lung cancer stem-like cells (LCSCs) derived from NSCLC patients.
  • To investigate the mechanism of action of CPTH6, focusing on its effects on cell viability, apoptosis, stemness markers, and histone acetyltransferase (HAT) inhibition.

Main Methods:

  • CPTH6 efficacy was assessed in patient-derived LCSCs and NSCLC cell lines.
  • Apoptosis induction, stemness marker expression, and protein acetylation levels were analyzed.
  • In vivo studies involved LCSC-derived xenografts to evaluate tumor growth inhibition and CSC content reduction.
  • The role of HAT inhibition was confirmed using various HAT inhibitors.

Main Results:

  • CPTH6 demonstrated preferential inhibition of LCSC growth compared to established NSCLC cells, primarily through apoptosis induction.
  • Differentiated LCSC progeny showed increased resistance to CPTH6 compared to undifferentiated LCSCs.
  • CPTH6 treatment reduced stemness markers in LCSCs and inhibited tumor growth and CSC content in vivo.
  • Inhibition of HAT by CPTH6 was confirmed both in vitro and in vivo, including tubulin acetylation.

Conclusions:

  • Histone acetyltransferase (HAT) inhibition, specifically by CPTH6, shows significant preferential efficacy against undifferentiated lung cancer stem-like cells.
  • CPTH6 exhibits potent anti-tumor activity in vitro and in vivo, reducing tumor growth and cancer stem cell populations.
  • HAT inhibition represents a promising therapeutic strategy for non-small cell lung cancer, particularly for targeting cancer stem cells.
Keywords:
HAT inhibitorsacetylationapoptosiscancer stem cellsnon-small cell lung cancer

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