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Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy

1
School of Medicine, Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202, USA
2
Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN 46202, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 972; https://doi.org/10.3390/cancers12040972
Received: 18 February 2020 / Revised: 31 March 2020 / Accepted: 7 April 2020 / Published: 14 April 2020
(This article belongs to the Special Issue PARPs, PAR and NAD Metabolism and Their Inhibitors in Cancer)
Poly-(ADP-ribose) polymerase 1 (PARP1) is commonly known for its vital role in DNA damage response and repair. However, its enzymatic activity has been linked to a plethora of physiological and pathophysiological transactions ranging from cellular proliferation, survival and death. For instance, malignancies with BRCA1/2 mutations heavily rely on PARP activity for survival. Thus, the use of PARP inhibitors is a well-established intervention in these types of tumors. However, recent studies indicate that the therapeutic potential of attenuating PARP1 activity in recalcitrant tumors, especially where PARP1 is aberrantly overexpressed and hyperactivated, may extend its therapeutic utility in wider cancer types beyond BRCA-deficiency. Here, we discuss treatment strategies to expand the tumor-selective therapeutic application of PARP inhibitors and novel approaches with predictive biomarkers to perturb NAD+ levels and hyperPARylation that inactivate PARP in recalcitrant tumors. We also provide an overview of genetic alterations that transform non-BRCA mutant cancers to a state of “BRCAness” as potential biomarkers for synthetic lethality with PARP inhibitors. Finally, we discuss a paradigm shift for the use of novel PARP inhibitors outside of cancer treatment, where it has the potential to rescue normal cells from severe oxidative damage during ischemia-reperfusion injury induced by surgery and radiotherapy. View Full-Text
Keywords: PARP Inhibitors; beta-lapachone; NQO1; PARG; NAMPT; cancer therapeutics; DNA repair; cMET PARP Inhibitors; beta-lapachone; NQO1; PARG; NAMPT; cancer therapeutics; DNA repair; cMET
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MDPI and ACS Style

Singh, N.; Pay, S.L.; Bhandare, S.B.; Arimpur, U.; Motea, E.A. Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy. Cancers 2020, 12, 972. https://doi.org/10.3390/cancers12040972

AMA Style

Singh N, Pay SL, Bhandare SB, Arimpur U, Motea EA. Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy. Cancers. 2020; 12(4):972. https://doi.org/10.3390/cancers12040972

Chicago/Turabian Style

Singh, Naveen, S. L. Pay, Snehal B. Bhandare, Udhaya Arimpur, and Edward A. Motea 2020. "Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy" Cancers 12, no. 4: 972. https://doi.org/10.3390/cancers12040972

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