title: Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer.
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.
authors.affiliation: Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
authors.forename: Nidal E
authors.initials: NE
authors.lastname: Muvarak
authors.affiliation: Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
authors.forename: Khadiza
authors.initials: K
authors.lastname: Chowdhury
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
authors.forename: Carine
authors.initials: C
authors.lastname: Robert
authors.affiliation: 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.
authors.forename: Eun Yong
authors.initials: EY
authors.lastname: Choi
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bellani
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Zeba N
authors.initials: ZN
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Vu H
authors.initials: VH
authors.lastname: Duong
authors.affiliation: Stevenson University, Stevenson, MD 21153, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Rutherford
authors.affiliation: Department of Radiation Oncology, University of Maryland, Baltimore, MD 21201, USA; University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201, USA.
authors.forename: Pratik
authors.initials: P
authors.lastname: Nagaria
authors.affiliation: 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.
authors.forename: Søren M
authors.initials: SM
authors.lastname: Bentzen
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Seidman
authors.affiliation: 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.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: 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.
authors.forename: Rena G
authors.initials: RG
authors.lastname: Lapidus
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA; Van Andel Research Institute, Grand Rapids, MI 49503.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: 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.
authors.forename: Feyruz V
authors.initials: FV
authors.lastname: Rassool
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D019175:DNA Methylation / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D010793:Phthalazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002843:Chromatin; D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: AML; DNA damage; DNA double-strand break; DNA repair; DNMT inhibitor; DNMT1; PARP; PARP inhibitor; PARP trapping; breast cancer