PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS
PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS
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DOI：
10.1002/nbm.3736
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发表时间：
2017-09-01
影响因子：
2.9
通讯作者：
Maxwell, Ross J.
中科院分区：
文献类型：
--
作者：
Almeida, Gilberto S.;Bawn, Carlo M.;Maxwell, Ross J.
多聚腺苷二磷酸核糖聚合酶（Poly（adenosine diphosphate ribose）polymerases，PARP）是一类多功能蛋白质，在许多细胞过程中发挥作用。也就是说，PARP 1和PARP 2已被证明参与DNA修复，因此是目前在临床试验中使用PARP抑制剂（如rucaparib）进行癌症治疗的有效靶标。通过定量分析烟酰胺腺苷二磷酸（NAD（+））光谱，使用质子磁共振波谱（H-1-MRS）研究rucaparib在体外和离体小鼠肝组织中的影响，以评估MRS作为PARP抑制剂反应生物标志物的潜力。SW 620（结直肠）和A2780（卵巢）癌细胞系以及PARP 1野生型（WT）和PARP 1敲除（KO）小鼠用rucaparib、替莫唑胺（甲基化剂）或两种药物的组合进行治疗。H-1-MRS光谱从肿瘤细胞和小鼠肝脏的高氯酸提取物中获得。与替莫唑胺治疗相比，PARP抑制剂治疗后两种细胞系均显示NAD（+）水平升高。与未处理的小鼠肝脏相比，Rucaparib处理后PARP 1 WT小鼠的肝脏提取物显示NAD（+）水平显著增加，替莫唑胺处理组的NAD（+）水平显著降低。rucaparib和替莫唑胺联合治疗不能预防替莫唑胺治疗引起的NAD（+）耗竭。H-1-MRS结果表明，NAD（+）水平可用作PARP抑制剂和甲基化剂治疗的生物标志物，并表明NAD（+）的体内测量将是有价值的。
Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (H-1-MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD(+)) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild-type (WT) and PARP1 knock-out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. H-1-MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD(+) levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD(+) levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD(+) levels in the temozolomide-treated group. The combination of rucaparib and temozolomide did not prevent the NAD(+) depletion caused by temozolomide treatment. The H-1-MRS results show that NAD(+) levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD(+) would be valuable.