信号转导通路: 细胞周期(Cell Cycle / Checkpoint) >> PARP >> PARP 抑制剂 >> ABT-888 (Veliparib)http://selleck.cn/abt-888-S1004.html
溶解度: DMSO ≥49mg/mL Water <1mg/mL Ethanol <1mg/mL
稳定性: at -20℃ 2 years
ABT-888有效抑制PARP，作用于PARP-1和PARP-2时Ki值分别为5.2和2.9 nmol。 
ABT-888抑制C41细胞，EC50为2 nmol，ABT-888和其他细胞毒素药剂联用作用于MX-1移植瘤模型时显示出强抗癌效力。  ABT-888降低肺癌H460细胞中克隆基因的存活率，且抑制DNA修复。ABT-888推迟NCI-H460 移植瘤模型的肿瘤生长。ABT-888在B16F10 和9L 移植瘤模型中抑制PARP，从而增强temozolomide的抗癌活性。  ABT-888和放射物联用减少肿瘤血管的形成。  在A375和 Colo829移植瘤模型中按肿瘤大小，每千克分别加3和12.5 mg ABT-888，可以看到肿瘤内95%以上PAR被抑制。  ABT-888和temozolomide联用用于治疗黑色素瘤和乳腺癌目前已经处于二期临床实验阶段。ABT-888最初是由Abbott实验室研究的。
 Donawho CK, et al, Clin Cancer Res, 2007, 13 (9), 2728-2737.
 Kummar S, et al, J Clin Oncol, 2009, 27(16), 2705-2711.
 Albert JM, et al, Clin Cancer Res, 2007, 13(10), 3033-3042.
 Kinders RJ, et al, Clin Cancer Res, 2008, 14(21), 6877-6885.
T47D breast cancer cells were pretreated with indicated concentrations of ABT-888
in vivo suppression of PAR formation by the PARP inhibitor ABT-888 uponinduction of DNA damage
Primary human lung fibroblast cells (MRC-5) were pre-treated with the indicated concentration of the PARP inhibitor ABT-888 for two hours. Oxidative DNA damage was induced by 500 µM H2O2 for 10 min and cellular PARP activity was measured by immuno-staining of poly(ADP)-ribose (PAR) (right panels). The in vivo effect of PARP inhibition was compared to cells without DNA damage induction and inhibitor (control) and H2O2-treated cells without inhibitor.
Average nuclear PAR staining intensities of more than 50 cells were statistically analysed by Kruskal-Wallis and the post-hoc Dunn’s Multiple Comparison tests (left panel). Asterisks indicate highly significant (p<1%) differences to H2O2-treated cells without PARP inhibitor. Thick horizontal bars mark medians and error bars the interquartile range.
Caption: 451 Lu is a melanoma cell line with high PARP expression that is resistant to temozolomide. Treatment with 25 µM ABT-888 greatly increased sensitivity to temozolomide compared to cells without ABT-888 treatment as measured by MTS assay.
Effect of ABT-888 on the viability of endometrial cancer cell line Hec50 and Ishikawa and ovarian cancer cell line SKOV3,Caov3 and PA-1 was detected by WST-1 method after 3 days treatment.
PARP inhibitors sensitize OVCAR-8 cells to FdUrd but not 5-FU. A, OVCAR-8 cells were exposed to the indicated concentrations of FdUrd (left) or 5-FU (right) along with vehicle, 3 mmol/L ABT-888 or 300 nmol/L AZD2281 for 24 hours. Following washing, ABT-888 and AZD2281 were readded to the plates initially exposed to these agents, and cells were cultured in the continued presence of ABT-888 or AZD2281 for 8 days until colonies formed. B, OVCAR-8 cells were exposed continuously to the indicated agents for 8 days. C, left, OVCAR-8 cells treated as in (A) except that the indicated concentrations of ABT-888 were used. Data shown are a representative experiment from 3 independent replicates. n =3 +SD. C, right, synergy between FdUrd and ABT-888 was calculated from the data in (C, left) using the median effect method and assuming that the agents are mutually exclusive. Combination index values less than 1 indicate synergy.
ABT-888 blocks recovery from FdUrd-induced cell-cycle arrest, enhances FdUrd-induced apoptosis, and maximally increases killing when present during and after FdUrd exposure. A, OVCAR-8 cells were incubated with vehicle, 3 mmol/L ABT-888, 25 mmol/L FdUrd, or 3 mmol/L ABT-888 and 25 mmol/L FdUrd for 24 hours. One set of cells was immediately stained with propidium iodide (0 hours). The remaining samples were washed, ABT-888 readded (to the samples initially exposed to ABT-888), and stained 24 and 48 hours later. B, cells were treated as in (A) and stained with Annexin V-FITC 24 and 48 hours after removal of FdUrd (with readdition of ABT-888 to samples initially exposed to ABT-888). Apoptosis was measured as the percentage of Annexin V-positive cells. C and D, OVCAR-8 cells were plated, treated with indicated concentrations of FdUrd and 3 mmol/L ABT-888 using the exposure schemes depicted in (C), and assayed for clonogenicity (D).
ABT-888 sensitizes multiple ovarian cancer cell lines but not normal cells to FdUrd. A, A2780, SKOV3ip, OVCAR-5, and OVCAR-3 ovarian cancer cells were treated with FdUrd for 24 hours in combination with vehicle or the indicated concentrations of ABT-888 for 24 hours. Following washing, ABT-888 was readded to samples initially exposed to ABT-888, and cells were cultured until colonies formed. Data shown are a representative experiment from 3 independent replicates. n=3+SD. B, OSEtsT/hTERT immortalized ovarian surface epithelial cells and WS1 human fibroblasts were treated with FdUrd with and without 3 mmol/L ABT-888. Cell viability was assessed via MTS assay. Data shown are the averages of 3 independent experiments. N=3+SEM.
ABT-888 sensitizes to FdUrd and temozolomide more effectively than to other chemotherapy agents. OVCAR-8 cells were treated with indicated concentrations of FdUrd, topotecan, melphalan, cisplatin, doxorubicin, gemcitabine, etoposide, and temozolomide in the presence or absence of 3 mmol/L ABT-888 for 24 hours. Following washing, ABT-888 was readded to samples initially exposed to ABT-888, and cells were cultured until colonies formed. Data shown are a representative experiment from 2 independent replicates. N=3+SD. Experiments with FdUrd, topotecan, melphalan, and temozolomide were independently replicated 3 times
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