Olaparib (AZD2281, Ku-0059436) (Synonyms: AZD 2281, Ku0059436)

Olaparib (AZD2281, Ku-0059436) is a potent and selective PARP inhibitor that specifically targets PARP1 and PARP2 (IC 50 = 5 nM and 1 nM, respectively). ^[1].It is an activator of autophagy and mitophagy.

Brca1-deficient cell lines were highly sensitive to PARP inhibition by Olaparib (AZD2281, Ku-0059436)^[1]. Olaparib (AZD2281, Ku-0059436) enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non-small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, Olaparib (AZD2281, Ku-0059436) enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival = 1.5 and 1.3) and DNA double-strand breaks persisted for at least 24 hours after treatment^[2]. PTEN-deficient endometrioid endometrial cancer cells are not responsive to PARP inhibitor Olaparib (AZD2281, Ku-0059436) alone, but instead show superior sensitivity to compound inhibition with PI3K inhibitor BKM120, as evidenced by reduced clonogenic cell growth and three-dimensional (3D) spheroid disintegration^[4].

Considerable inhibition of tumor volumes as compared with that of the TMZ alone group was observed for the TMZ plus Olaparib (AZD2281, Ku-0059436)combination. This equated to over 80% tumor growth inhibition throughout the entire terminal phase of the study between TMZ treatment and the combination^[1]. The PARP inhibitor AZD2281 (olaparib) showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or Olaparib (AZD2281, Ku-0059436)^[3]. Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in strongly increased survival. Long-term treatment with Olaparib (AZD2281, Ku-0059436) in this model did result in the development of drug resistance^[5]. DNA damage denoted by γH2AX foci was completely undetectable in primordial follicles of control animals but was observed in 10% of surviving primordial follicle oocytes in mice treated with Olaparib (AZD2281, Ku-0059436) alone^[7]. When explored the possible combination of the PAPRi Olaparib (AZD2281, Ku-0059436) with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer.The administration of Olaparib (AZD2281, Ku-0059436) could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Olaparib (AZD2281, Ku-0059436) could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8+ T cells in tumor tissue^[6].

References:
[1]: Menear KA, Adcock C,et,al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008 Oct 23;51(20):6581-91. doi: 10.1021/jm8001263. Epub 2008 Sep 19. PMID: 18800822.
[2]: Senra JM, Telfer BA, et,al. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. Mol Cancer Ther. 2011 Oct;10(10):1949-58. doi: 10.1158/1535-7163.MCT-11-0278. Epub 2011 Aug 8. PMID: 21825006; PMCID: PMC3192032.
[3]: Yasukawa M, Fujihara H, et,al. Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo. Int J Mol Sci. 2016 Feb 24;17(3):272. doi: 10.3390/ijms17030272. PMID: 26927065; PMCID: PMC4813136.
[4]: Bian X, Gao J, et,al. PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene. 2018 Jan 18;37(3):341-351. doi: 10.1038/onc.2017.326. Epub 2017 Sep 25. PMID: 28945226; PMCID: PMC5799770.
[5]: Rottenberg S, Jaspers JE, et,al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29. PMID: 18971340; PMCID: PMC2579381.
[6]: Sun R, Luo H, et,al.Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice. Mol Ther. 2021 Jan 6;29(1):60-74. doi: 10.1016/j.ymthe.2020.09.034. Epub 2020 Sep 26. PMID: 33010818; PMCID: PMC7791086.
[7]: Winship AL, Griffiths M, et,al. The PARP inhibitor, olaparib, depletes the ovarian reserve in mice: implications for fertility preservation. Hum Reprod. 2020 Aug 1;35(8):1864-1874. doi: 10.1093/humrep/deaa128. PMID: 32604417.