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

doi:10.1016/j.ccell.2016.09.002

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

Cancer Cell. 2016 Oct 10;30(4):637-650. doi: 10.1016/j.ccell.2016.09.002.

Authors

Nidal E Muvarak¹, Khadiza Chowdhury¹, Limin Xia², Carine Robert¹, Eun Yong Choi³, Yi Cai², Marina Bellani⁴, Ying Zou⁵, Zeba N Singh⁵, Vu H Duong³, Tyler Rutherford⁶, Pratik Nagaria¹, Søren M Bentzen⁷, Michael M Seidman⁴, Maria R Baer⁸, Rena G Lapidus³, Stephen B Baylin⁹, Feyruz V Rassool¹⁰

Affiliations

¹ Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
² The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
³ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
⁴ Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
⁵ Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁶ Stevenson University, Stevenson, MD 21153, USA.
⁷ Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁸ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA; Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
⁹ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA; Van Andel Research Institute, Grand Rapids, MI 49503.
¹⁰ Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA. Electronic address: frassool@som.umaryland.edu.

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.

Keywords: AML; DNA damage; DNA double-strand break; DNA repair; DNMT inhibitor; DNMT1; PARP; PARP inhibitor; PARP trapping; breast cancer.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Line, Tumor
Chromatin / metabolism
DNA Breaks, Double-Stranded
DNA Methylation / drug effects*
Drug Synergism
Female
Humans
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / metabolism
Male
Mice
Mice, Inbred NOD
Mice, Nude
Phthalazines / pharmacology
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Triple Negative Breast Neoplasms / drug therapy*
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism
Xenograft Model Antitumor Assays

Substances

Chromatin
Phthalazines
Poly(ADP-ribose) Polymerase Inhibitors
talazoparib
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding