ABT-888 (Veliparib) is an effective inhibitor of PARP1 and PARP2 with Ki values of 5.2 and 2.9nM respectively [1]. PARP is involved in DNA repair, and elevated PARP levels can lead to resistance to cytotoxic chemotherapy and radiotherapy [2]. ABT-888 can be used to induce autophagy and apoptosis in tumor cells [3].
In vitro, ABT-888 (0-50μM; 72h) could reduce the cell viability of melanoma cell lines (A375 and A375R) in a dose-dependent manner, reaching the maximum effect within the range of 25-50μM and showing pro-apoptotic activity [4]. Treatment with ABT-888 (10μM; 6h) significantly improved the reduction in cell viability induced by 1000μM sulindac (SM), and decreased the pADPr content (representing PARP-1 activity) in the cells, while ABT-888 did not affect the cell viability after treatment with 100μM SM [5].
In vivo, ABT-888 (25mg/kg/day for 14 days; oral gavage) and carboplatin alone or in combination delayed tumor growth in mice with VC8 xenograft tumor models and reduced tumor mass. The combination therapy was the most effective in slowing tumor growth [6]. The combination (AG014699/PF-02341066 and ABT-888 (5mg/kg/day; five times per week for 26 days; oral)/Foretinib) significantly reduced tumor growth in MDA-MB-231 xenograft tumor model mice, increased tumor cell apoptosis and DNA damage [7].
References:
[1] Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13(9):2728-2737.
[2] Li X, Delzer J, Voorman R, de Morais SM, Lao Y. Disposition and drug-drug interaction potential of veliparib (ABT-888), a novel and potent inhibitor of poly(ADP-ribose) polymerase. Drug Metab Dispos. 2011;39(7):1161-1169.
[3] Lin F, De Gooijer M C, Roig E M, et al. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy[J]. Clinical cancer research, 2014, 20(10): 2703-2713.
[4] Fratangelo F, Camerlingo R, Carriero M V, et al. Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells[J]. International Journal of Oncology, 2018, 53(3): 1149-1159.
[5] Liu F, Jiang N, Xiao ZY, et al. Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo. PeerJ. 2016;4:e1890.
[6] Clark C C, Weitzel J N, O'Connor T R. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models[J]. Molecular cancer therapeutics, 2012, 11(9): 1948-1958.
[7] Du Y, Yamaguchi H, Wei Y, et al. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat Med. 2016;22(2):194-201.
ABT-888 (Veliparib)是一种有效的PARP1和PARP2抑制剂，Ki分别为5.2和2.9nM [1]。PARP参与DNA修复，PARP水平升高可导致对细胞毒性化疗和放疗的抗性 [2]。ABT-888可用于诱导肿瘤细胞自噬和凋亡 [3]。
在体外，ABT-888（0-50μM; 72h）能够以剂量依赖性方式降低黑色素瘤细胞系（A375和A375R）中的细胞活力，在25-50μM浓度范围内达到最大效果并表现出促凋亡活性 [4]。ABT-888（10μM; 6h）处理显著改善了1000μM硫芥（SM）诱导的HaCaT细胞的细胞活力的降低，并降低细胞中的pADPr含量(代表PARP-1活性)，而ABT-888不影响100μM SM处理后细胞的活力 [5]。
在体内，ABT-888（25mg/kg/day for 14 days; oral gavage）和carboplatin单独或联合治疗延缓了VC8异种移植肿瘤模型小鼠的肿瘤生长并减少了肿瘤质量，联合治疗在减缓肿瘤生长方面最有效 [6]。联合使用（AG014699/PF-02341066和ABT-888（5mg/kg/day; five times per week for 26 days; oral）/Foretinib）显著减少了MDA-MB-231异种移植肿瘤模型小鼠的肿瘤生长，增加了肿瘤细胞的凋亡和DNA损伤 [7]。