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Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy

Jingjing Li1, Dapeng Hao1, Li Wang1,2

  • 1Cancer Center, Faculty of Health Sciences, University of Macau, Macau, China.

Scientific Reports
|June 24, 2017
PubMed

Insights

Epigenetic targeting drugs (ETDs) combined with DNA targeting drugs (DTDs) show promise for solid tumors. This combination enhances drug efficacy by increasing chromatin accessibility, leading to improved tumor cell death.

Area of Science:

  • Oncology
  • Cancer Therapeutics
  • Epigenetics

Background:

  • Epigenetic therapy targets aberrant epigenetic modifications in cancer-related genes using epigenetic targeting drugs (ETDs).
  • Clinical trials of ETDs in solid tumors have yielded limited success, unlike in hematopoietic cancers.
  • A meta-analysis suggests promising curative effects when ETDs are combined with DNA targeting drugs (DTDs).

Purpose of the Study:

  • To investigate the synergistic mechanism of combining ETDs and DTDs for solid tumor therapy.
  • To evaluate the therapeutic effects of this combination in both cell lines and mouse models.

Main Methods:

  • Utilized cell lines and mouse engrafted tumors to study the combination therapy.
  • Investigated the effect of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors on chromatin accessibility.
  • Assessed DNA damage and cell death induction by cisplatin (CP) and doxorubicin (Dox).

Main Results:

  • HDAC and DNMT inhibitors increase chromatin accessibility to CP and Dox via global chromatin decompaction.
  • The combination of ETDs and DTDs enhances DTD-induced DNA damage and cell death.
  • Pretreatment with ETDs increased the sensitivity of engrafted tumors in SCID mice to irradiation (IR) or CP.

Conclusions:

  • The combination of DTDs (including irradiation) and ETDs offers a promising strategy for clinical solid tumor therapy.
  • ETDs alone have limited therapeutic effects, highlighting the importance of combination strategies.
  • Enhanced chromatin accessibility is a key mechanism underlying the synergistic effects of ETD-DTD combinations.

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