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Review
. 2011 Jan-Feb;35(1):7-50.
doi: 10.1016/j.currproblcancer.2010.12.002.

PARP inhibitor treatment in ovarian and breast cancer

Marcie K Weil  1 , Alice P Chen
Affiliations
Review

PARP inhibitor treatment in ovarian and breast cancer

Marcie K Weil et al. Curr Probl Cancer. 2011 Jan-Feb.
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Causes of DNA damage, Types of DNA Repair, Cellular Consequences
Reprinted by permission from Macmillan Publishers Ltd: Nature 22;362(6422):709–15, copyright 2001. [9]
Fig. 2
Fig. 2. Proteins involved in Homologous Recombination
When DSBs occur, ATM and CHEK2 kinases mobilize proteins such as BRCA 1 protein. BRCA 2 carries Rad51, the recombination enzyme, to the DSB site. A complex of Fanconi anemia proteins, A, C, D2, E, F, and G, cause the ubiquitinization of D2 protein and the subsequent association of D2 with BRCA 1. All of this ultimately leads to repair the DSB with minimal error in the DNA. Reprinted with permission [12], Copyright © 2003 Massachusetts Medical Society. All rights reserved.
Fig. 3
Fig. 3. Gene Conversion Homologous Recombination
Gene conversion uses the homologous sequence, usually within the sister chromatid, as the template, and thereby usually repairs without error. Reprinted from Trends in Biochemical Sciences, 24(7), Haber JE, “DNA recombination: the replication connection,” 271–5, Copyright 1999, with permission from Elsevier. [13]
Fig. 4
Fig. 4. Structure and activity of PARP
PARP 1 is active in its homodimeric form. It has 3 functional domains, the DNA-binding domain (DBD), the automodification domain (AD), and the catalytic domain. The amino-terminal DBD is 42 kDa. It contains 3 zinc fingers, two that bind PARP 1 to DNA breaks, and a third that couples DNA damage-induced changes in the DBD to catalytic activity. The 16 kDa AD portion contains glutamate and lysine amino acids that accept ADP-ribose units, resulting in self poly (ADP-ribosyl)ation. The AD unit houses the BRCA 1 carboxyl-terminal (BRCT) repeat motif, similar to DNA sequences in other proteins involved in DNA repair. The C-terminal catalytic domain is 55 KDa. It holds the signature sequence containing the most conserved sequence of the PARP family. In this domain ADP-ribose transferase facilitates the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to protein acceptors within this domain. PARP proteins are activated by DNA strand breaks. PARP 1 is active in a homodimeric state. It then synthesizes poly(ADP) ribose (pADPr, PAR) and transfers it to acceptor proteins. The acceptor proteins can be located on PARP 1 itself or on other proteins involved in DNA repair. The negative charge of PAR causes PARP 1 to lose its affinity for DNA. PAR recruits other repair proteins to the damaged DNA site. Poly(ADP-ribose) glycohydrolase (PARG) and possibly ADP-ribose hyrolase 3 (ARH3) break pADPr into ADP-ribose molecules, which are metabolized further to AMP. The increased AMP:ATP ratio triggers the metabolic sensor AMP-activated protein kinase (AMPK). MTORC1 is thereby inhibited, inducing autophagy. [30] Thus cellular energy homeostasis is regulated. In the process of making PAR, NAD+ is converted to nicotinamide. To replenish the NAD+ from nicotinamide, phosphoribosylpyrophosphate (PRPP) and ATP are converted to AMP and pyrophosphate. In the case of extreme DNA damage, as with ischemia, PARP 1 hyperactivation results in depletion of NAD+ and ATP, resulting in cell death by necrosis or apoptosis. PAR covalently and noncovalently binds proteins that work in the repair of DNA or works on these proteins via pADPr-binding proteins. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer, 10(4):293–301, copyright 2010. [4]
Fig. 5
Fig. 5. Multiple mechanisms of action of PARP Inhibitors
PARP 1 inhibitors decreased tumor growth and tumor vasculature through decreased expression of HIF-1α, activation protein-1 (AP-1), and NF-κB, and other genes involved in carcinogenesis and inflammation. Reprinted thanks to Cancer Research, AACR 2006. [37]
Fig. 6
Fig. 6
a. Normal Wnt signaling. b. exposure to TNKS inhibitor
Fig. 7
Fig. 7. PARP 1 inhibition leads to collapsed replication forks and need for homologous repair for cell survival
Reprinted by permission from Macmillan Publishers Ltd: Nature, 14;434(7035):913–7, copyright 2005. [46]
Fig 8
Fig 8. Disease-Free Survival and Overall Survival in BRCA-like profile and Non-BRCA-like profile
Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved. Konstantinopoulos PA, et al. J Clin Oncol 28(22), 2010: 3555–61. [80]
Figure 9
Figure 9. AG 014699 (PF01367338) Pfizer
(8-fluoro-2-(4-methylaminomethylphenyl)-1,3,4,5-tetrahydroazepino[5,4,3-cd]indol-6-one). [105]
Figure 10
Figure 10. Olaparib (AZD 2281, KU-0059436) AstraZeneca
4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one C24H23FN4O3 [110]
Figure 11
Figure 11
Iniparib (BSI 201, NSC-746045; IND-71677) sanofi-aventis [118] http://en.wikipedia.org/wiki/File:Iniparib.svg
Figure 12
Figure 12. Veliparib (ABT888)
Abbott Laboratories. 2-((R)-2-Methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide. C13H16N4O [122] http://upload.wikimedia.org/wikipedia/commons/d/da/Veliparib_skeletal.svg
Figure 13
Figure 13. Effect of 53BP1 on HR
See this image and copyright information in PMC

References

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    1. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 9;361(2):123–134. - PubMed
    1. Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD, 2nd, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol. 2010 Aug 1;28(22):3570–3576. - PMC - PubMed
    1. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010 Apr;10(4):293–301. - PMC - PubMed
    1. Hirschhorn R. In vivo reversion to normal of inherited mutations in humans. J Med Genet. 2003 Oct;40(10):721–728. - PMC - PubMed

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