Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer

Nidal E. Muvarak, Khadiza Chowdhury, Limin Xia, Carine Robert, Eun Yong Choi, Yi Cai, Marina Bellani, Ying Zou, Zeba N. Singh, Vu H. Duong, Tyler Rutherford, Pratik Nagaria, Søren M. Bentzen, Michael M. Seidman, Maria R. Baer, Rena G. Lapidus, Stephen B. Baylin, Feyruz V. Rassool

Research output: Contribution to journalArticlepeer-review

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) are clinically effective predominantly for BRCA-mutant tumors. We introduce a mechanism-based strategy to enhance PARPi efficacy based on DNA damage-related binding between DNA methyltransferases (DNMTs) and PARP1. In acute myeloid leukemia (AML) and breast cancer cells, DNMT inhibitors (DNMTis) alone covalently bind DNMTs into DNA and increase PARP1 tightly bound into chromatin. Low doses of DNMTis plus PARPis, versus each drug alone, increase PARPi efficacy, increasing amplitude and retention of PARP1 directly at laser-induced DNA damage sites. This correlates with increased DNA damage, synergistic tumor cytotoxicity, blunting of self-renewal, and strong anti-tumor responses, in vivo in unfavorable AML subtypes and BRCA wild-type breast cancer cells. Our combinatorial approach introduces a strategy to enhance efficacy of PARPis in treating cancer.

Original languageEnglish (US)
Pages (from-to)637-650
Number of pages14
JournalCancer cell
Volume30
Issue number4
DOIs
StatePublished - Oct 10 2016
Externally publishedYes

Keywords

  • AML
  • DNA damage
  • DNA double-strand break
  • DNA repair
  • DNMT inhibitor
  • DNMT1
  • PARP
  • PARP inhibitor
  • PARP trapping
  • breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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