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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

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 language	English (US)
Pages (from-to)	637-650
Number of pages	14
Journal	Cancer cell
Volume	30
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2016.09.002
State	Published - Oct 10 2016

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
Cancer Research

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10.1016/j.ccell.2016.09.002

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Muvarak, N. E., Chowdhury, K., Xia, L., Robert, C., Choi, E. Y., Cai, Y., Bellani, M., Zou, Y., Singh, Z. N., Duong, V. H., Rutherford, T., Nagaria, P., Bentzen, S. M., Seidman, M. M., Baer, M. R., Lapidus, R. G., Baylin, S. B., & Rassool, F. V. (2016). Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer. Cancer cell, 30(4), 637-650. https://doi.org/10.1016/j.ccell.2016.09.002

Muvarak, NE, Chowdhury, K, Xia, L, Robert, C, Choi, EY, Cai, Y, Bellani, M, Zou, Y, Singh, ZN, Duong, VH, Rutherford, T, Nagaria, P, Bentzen, SM, Seidman, MM, Baer, MR, Lapidus, RG, Baylin, SB & Rassool, FV 2016, 'Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents – A Potential Therapy for Cancer', Cancer cell, vol. 30, no. 4, pp. 637-650. https://doi.org/10.1016/j.ccell.2016.09.002

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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.",

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AU - Seidman, Michael M.

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

Abstract

Keywords

ASJC Scopus subject areas

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