PARP Inhibitors

Overview

Journal Hered Cancer Clin Pract

Publisher Biomed Central

Specialty Oncology

Date 2015 Jan 22

PMID 25606064

Citations 20

Authors

Maheen Anwar

Hafiz Muhammad Aslam

Shahzad Anwar

Affiliations

Soon will be listed here.

Abstract

Poly (ADP-ribose) polymerases, abbreviated as PARPs, are a group of familiar proteins that play a central role in DNA repair employing the base excision repair (BER) pathway. There about 17 proteins in this family out of which the primary nuclear PARPs are PARP-1, PARP-2, PARP-3, and tankyrases 1 and 2 (PARP-5a and -5b) .The PARP family members are known to engage in a wide range of cellular activities, for example, DNA repair, transcription, cellular signaling, cell cycle regulation and mitosis amongst others. The chief functional units of PARP-1 are an amino terminal DNA binding domain (DBD), a central auto modification domain (AMD), and a carboxyl-terminal catalytic domain (CD). PARP inhibitors are currently undergoing clinical trials as targeted treatment modalities of breast, uterine, colorectal and ovarian cancer. This review summarizes current insights into the mechanism of action of PARP inhibitors, its recent clinical trials, and potential next steps in the evaluation of this promising class of anti-cancer drugs.

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References

Ferraris D . Evolution of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. From concept to clinic. J Med Chem. 2010; 53(12):4561-84. DOI: 10.1021/jm100012m. View

Hakme A, Wong H, Dantzer F, Schreiber V . The expanding field of poly(ADP-ribosyl)ation reactions. 'Protein Modifications: Beyond the Usual Suspects' Review Series. EMBO Rep. 2008; 9(11):1094-100. PMC: 2581850. DOI: 10.1038/embor.2008.191. View

Masutani M, Nakagama H, Sugimura T . Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease. Cell Mol Life Sci. 2005; 62(7-8):769-83. DOI: 10.1007/s00018-004-4509-x. View

Davar D, Beumer J, Hamieh L, Tawbi H . Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 2012; 19(23):3907-21. PMC: 3421454. DOI: 10.2174/092986712802002464. View

Luo X, Kraus W . On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 2012; 26(5):417-32. PMC: 3305980. DOI: 10.1101/gad.183509.111. View

Mendes-Pereira A, Martin S, Brough R, McCarthy A, Taylor J, Kim J . Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2010; 1(6-7):315-22. PMC: 3378149. DOI: 10.1002/emmm.200900041. View

Konstantinopoulos P, Spentzos D, Karlan B, Taniguchi T, Fountzilas E, Francoeur N . Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010; 28(22):3555-61. PMC: 2917311. DOI: 10.1200/JCO.2009.27.5719. View

McCabe N, Turner N, Lord C, Kluzek K, Bialkowska A, Swift S . Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006; 66(16):8109-15. DOI: 10.1158/0008-5472.CAN-06-0140. View

Hassa P, Hottiger M . The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front Biosci. 2007; 13:3046-82. DOI: 10.2741/2909. View

10.

Huber A, Bai P, Menissier de Murcia J, de Murcia G . PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair (Amst). 2004; 3(8-9):1103-8. DOI: 10.1016/j.dnarep.2004.06.002. View

11.

Bryant H, Schultz N, Thomas H, Parker K, Flower D, Lopez E . Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005; 434(7035):913-7. DOI: 10.1038/nature03443. View

12.

Ame J, Spenlehauer C, de Murcia G . The PARP superfamily. Bioessays. 2004; 26(8):882-93. DOI: 10.1002/bies.20085. View

13.

Fong P, Boss D, Yap T, Tutt A, Wu P, Mergui-Roelvink M . Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009; 361(2):123-34. DOI: 10.1056/NEJMoa0900212. View

14.

Kummar S, Chen A, Parchment R, Kinders R, Ji J, Tomaszewski J . Advances in using PARP inhibitors to treat cancer. BMC Med. 2012; 10:25. PMC: 3312820. DOI: 10.1186/1741-7015-10-25. View

15.

Rouleau M, Patel A, Hendzel M, Kaufmann S, Poirier G . PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010; 10(4):293-301. PMC: 2910902. DOI: 10.1038/nrc2812. View

16.

Russo A, Kwon H, Burgan W, Carter D, Beam K, Weizheng X . In vitro and in vivo radiosensitization of glioblastoma cells by the poly (ADP-ribose) polymerase inhibitor E7016. Clin Cancer Res. 2009; 15(2):607-12. PMC: 6322204. DOI: 10.1158/1078-0432.CCR-08-2079. View

17.

Miknyoczki S, Chang H, Grobelny J, Pritchard S, Worrell C, McGann N . The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol Cancer Ther. 2007; 6(8):2290-302. DOI: 10.1158/1535-7163.MCT-07-0062. View

18.

Pacher P, Szabo C . Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc Drug Rev. 2007; 25(3):235-60. PMC: 2225457. DOI: 10.1111/j.1527-3466.2007.00018.x. View

19.

Munoz-Gamez J, Martin-Oliva D, Aguilar-Quesada R, Canuelo A, Nunez M, Valenzuela M . PARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis. Biochem J. 2004; 386(Pt 1):119-25. PMC: 1134773. DOI: 10.1042/BJ20040776. View

20.

Mota R, Sanchez-Bueno F, Saenz L, Hernandez-Espinosa D, Jimeno J, Tornel P . Inhibition of poly(ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury. Lab Invest. 2005; 85(10):1250-62. DOI: 10.1038/labinvest.3700326. View