Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy
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, mal...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-04-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/4/972 |
| _version_ | 1797570648047878144 |
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| author | Naveen Singh S. Louise Pay Snehal B. Bhandare Udhaya Arimpur Edward A. Motea |
| author_facet | Naveen Singh S. Louise Pay Snehal B. Bhandare Udhaya Arimpur Edward A. Motea |
| author_sort | Naveen Singh |
| collection | DOAJ |
| description | 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 <i>BRCA1/2</i> 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<sup>+</sup> 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. |
| first_indexed | 2024-03-10T20:28:37Z |
| format | Article |
| id | doaj.art-fb1ed131cd8747c89459fcd45bef7773 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T20:28:37Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fb1ed131cd8747c89459fcd45bef77732023-11-19T21:37:29ZengMDPI AGCancers2072-66942020-04-0112497210.3390/cancers12040972Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer TherapyNaveen Singh0S. Louise Pay1Snehal B. Bhandare2Udhaya Arimpur3Edward A. Motea4School of Medicine, Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202, USASchool of Medicine, Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202, USASchool of Medicine, Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202, USASchool of Medicine, Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202, USASchool of Medicine, Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN 46202, USAPoly-(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 <i>BRCA1/2</i> 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<sup>+</sup> 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.https://www.mdpi.com/2072-6694/12/4/972PARP Inhibitorsbeta-lapachoneNQO1PARGNAMPTcancer therapeutics |
| spellingShingle | Naveen Singh S. Louise Pay Snehal B. Bhandare Udhaya Arimpur Edward A. Motea Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy Cancers PARP Inhibitors beta-lapachone NQO1 PARG NAMPT cancer therapeutics |
| title | Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy |
| title_full | Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy |
| title_fullStr | Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy |
| title_full_unstemmed | Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy |
| title_short | Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy |
| title_sort | therapeutic strategies and biomarkers to modulate parp activity for targeted cancer therapy |
| topic | PARP Inhibitors beta-lapachone NQO1 PARG NAMPT cancer therapeutics |
| url | https://www.mdpi.com/2072-6694/12/4/972 |
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