PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs
<p>Structural characteristics of PARP1 and PARP1-based DNA repair. (<b>a</b>) Schematic representation of human PARP1 molecular architecture; (<b>b</b>) Structural process of PARP1-mediated DNA repair. After DNA-binding domain (DBD, blue ball) of PARP1 senses and binds damaged DNA, the NAD<sup>+</sup> will be cleaved into ADP-ribose and nicotinamide, which are catalyzed by the catalytic domain (CAT, yellow ball) of PARP1. Then, poly (ADP-ribose) (pADPr) is synthesized on the acceptor PARP1 through the combination of ADP-ribose, assisted by the catalysis of CAT too. Subsequently, PARP1 leaves damaged DNA, due to the dense negative charge of pADPr, allowing the recruitment of related repair proteins and replication. In chemical formulae, domains in yellow represents active domains of PARP1, while blue and black parts represent NAD<sup>+</sup>. Hydroxyl of Ser904 and carbonyl and NH group of Gly863 in PARP1 interact with the amide moiety of NAD<sup>+</sup> via hydrogen bonding interaction, while Tyr907 of PARP1 via π–π stacking interaction. The curved arrows in blue represent the nucleophilic attack by the 2′-hydroxyl of the acceptor site in PARP1, and the release of the nicotinamide procedures; AD, orange ball; WGR, red ball. (<b>c</b>) The PARP1/damaged DNA crystal structure. Zn1, dark green; Zn2, silver (left); Zn3, light green; BRCT, silver (right); ART, dark yellow; HD, light yellow; red, WGR [<a href="#B4-ijms-18-02111" class="html-bibr">4</a>,<a href="#B18-ijms-18-02111" class="html-bibr">18</a>,<a href="#B19-ijms-18-02111" class="html-bibr">19</a>].</p> "> Figure 2
<p>Cancer cells fate induced by different levels of PARP1-related DNA repair in tumor. PARP1 regulated various pathways due to the degree of DNA lesion in tumor. To survive, cancer cells will activate PARP1 to repair mildly damaged DNA, and harbor carcinogenetic genetic mutations via maintaining DNA lesions. In case of excessive DNA lesions, normal PARP1 activation will cause insufficient DNA repair, subsequently leading to cancer cell apoptosis. This may be a more desirable result of cancer cells in anticancer therapy, because apoptosis cells will then be cleared by macrophages rapidly. On the other hand, overactivation of PARP1 will lead to further mutagenesis, metastasis, and energy-depleted necrosis and autophagy of tumors. Necrosis will then further induce inflammation, which is another important carcinogenetic factor. Inhibition of PARP1 overactivation by PARP1 inhibitors will transform cells’ fate to apoptosis, subsequently reduce further mutagenesis, metastasis, autophagy, necrosis, and tumor-promoting inflammation (dashed arrow) [<a href="#B4-ijms-18-02111" class="html-bibr">4</a>,<a href="#B14-ijms-18-02111" class="html-bibr">14</a>,<a href="#B18-ijms-18-02111" class="html-bibr">18</a>].</p> "> Figure 3
<p>The multifunction of PARP1 in tumorigenesis. PARP1 is considered to promote tumor development potentially through many pathways. Briefly, PARP1 regulates gene transcription through interacting with transcription factors, transcription machinery, and chromatin modulators. Hyperactivated PARP1 upregulates inflammatory signal factors in tumors. Also, PARP1 modulates cancer cellular life cycle via regulating cellular mitosis and cell death pathways, including apoptosis, necrosis, and necroptosis. PARP1 activates pro-angiogenic factors and induces angiogenesis and metastasis in tumors.</p> ">
Abstract
:1. Introduction
2. PARP1 Structure and Expression in Carcinomas
3. PARP1 Function and Mechanism in Carcinomas
3.1. Multifaceted Function on DNA Repair
3.2. PARP1 in Gene Transcription
3.3. PARP1 in Tumor-Promoting Inflammation
3.4. PARP1 in Cell Cycling Regulation
3.5. PARP1 in Metastasis and Angiogenesis
4. PARP1 Inhibitors against Carcinomas
5. Conclusions and Future Perspectives
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Cancer Types | Expression of PARP1 |
---|---|
Breast Cancer | Up-regulated |
Ovarian Cancer | Up-regulated |
Uterine Cancer | Up-regulated |
Lung Cancer | Up-regulated |
Skin Cancer | Up-regulated |
Non-Hodgkin’s Lymphoma | Up-regulated |
Glioblastoma Multiforme | Up-regulated |
Prostate Cancer | Up-regulated |
Ewing’s Sarcoma | Up-regulated |
Colorectal Cancer | Up-regulated |
Pediatric Central Nervous System Cancer | Up-regulated |
Testicular Germ Cell Tumor | Up-regulated |
Drug | Structure | Active Structural Group | Biophysical Parameters (PARP1) | Well Studied Cancer Types | Typical Clinical Trials No. (The Latest Stage) | Phase | REF |
---|---|---|---|---|---|---|---|
Olaparib (AZD2281) | Amide motif enclosed in cyclic ring | IC50 = 5 nM | Ovarian carcinoma | NCT02476968 (Phase 4) | 1–4 | [1,73] | |
Breast carcinoma | NCT02032823 (Phase 3) | 1–3 | |||||
Prostate carcinoma | NCT02987543 (Phase 3) | 1–3 | |||||
Pancreatic carcinoma | NCT02184195 (Phase 3) | 1–3 | |||||
Ewing’s sarcoma | NCT01583543 (Phase 2) | 1–2 | |||||
Gastric carcinoma | NCT01924533 (Phase 3) | 1–3 | |||||
Lung carcinoma | NCT03009682 (Phase 2) | 1–2 | |||||
Germ Cell Tumor | NCT02533765 (Phase 2) | 1–2 | |||||
Colorectal carcinoma | NCT00912743 (Phase 2) | 1–2 | |||||
Unknown solid tumors | NCT03233204 (Phase 2) | 1–2 | |||||
Niraparib (MK-4827) | Conventional embedded primary amide | IC50 = 3.2 nM | Ovarian carcinoma | NCT01847274 (Phase 3) | 1–3 | [76,93] | |
Breast carcinoma | NCT01905592 (Phase 3) | 1–3 | |||||
Endometrial carcinoma | NCT03016338 (Phase 2) | 1–2 | |||||
Uveal melanoma | NCT03207347 (Phase 2) | 1–2 | |||||
Fallopian tube carcinoma | NCT02657889 (Phase 2) | 1–2 | |||||
Peritoneal carcinoma | NCT02657889 (Phase 2) | 1–2 | |||||
Rucaparib (AG-014669, PF-01367338) | Amide motif enclosed in cyclic ring | IC50 = 1.4 nM | Ovarian carcinoma | NCT02855944 (Phase 3) | 1–3 | [78,80,96] | |
Fallopian tube carcinoma | NCT02855944 (Phase 3) | 1–3 | |||||
Peritoneal carcinoma | NCT01968213 (Phase 3) | 1–3 | |||||
Prostate carcinoma | NCT02975934 (Phase 3) | 1–3 | |||||
Pancreatic carcinoma | NCT02042378 (Phase 2) | 1–2 | |||||
Breast carcinoma | NCT02505048 (Phase 2) | 1–2 | |||||
Veliparib (ABT-888) | Conventional embedded primary amide | Ki = 5.2 nM | Breast carcinoma | NCT02032277 (Phase 3) | 1–3 | [82,97,98] | |
Ovarian carcinoma | NCT02470585 (Phase 3) | 1–3 | |||||
Non-small cell lung carcinoma | NCT02106546 (Phase 3) | 1–3 | |||||
Solid tumors | NCT01193140 (Phase 2) | 1–2 | |||||
Testicular carcinoma | NCT02860819 (Phase 2) | 1–2 | |||||
Talazoparib (BMN-673) | Amide motif enclosed in cyclic ring | IC50 = 1.2 nM | Breast carcinoma | NCT01945775 (Phase 3) | 1–3 | [85,86,99,100] | |
Prostate carcinoma | NCT03148795 (Phase 2) | 1–2 | |||||
Ovarian carcinoma | NCT02326844 (Phase 2) | 1–2 | |||||
Endometrial carcinoma | NCT02127151 (Phase 2) | 1–2 | |||||
Acute Myeloid Leukemia | NCT02878785 (Phase 2) | 1–2 |
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Wang, L.; Liang, C.; Li, F.; Guan, D.; Wu, X.; Fu, X.; Lu, A.; Zhang, G. PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs. Int. J. Mol. Sci. 2017, 18, 2111. https://doi.org/10.3390/ijms18102111
Wang L, Liang C, Li F, Guan D, Wu X, Fu X, Lu A, Zhang G. PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs. International Journal of Molecular Sciences. 2017; 18(10):2111. https://doi.org/10.3390/ijms18102111
Chicago/Turabian StyleWang, Luyao, Chao Liang, Fangfei Li, Daogang Guan, Xiaoqiu Wu, Xuekun Fu, Aiping Lu, and Ge Zhang. 2017. "PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs" International Journal of Molecular Sciences 18, no. 10: 2111. https://doi.org/10.3390/ijms18102111