Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP‑ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells.
Inhibition of poly(ADP-ribose) polymerase-1 or poly(ADP‑ribose) glycohydrolase individually, but not in combination, leads to improved chemotherapeutic efficacy in HeLa cells.
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DOI：
10.3892/ijo.2012.1740
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发表时间：
2013-02
影响因子：
5.2
通讯作者：
Koh DW
中科院分区：
文献类型：
--
作者：
Feng X;Koh DW
聚腺苷二磷酸核糖（PAR）的基因组保护作用已确定PAR聚合酶-1（PARP-1）和PAR糖水解酶（PARG），这两种负责PAR合成和水解的酶，作为化疗靶点。之前已经在化疗中单独评估了每一种，但PARP-1和PARG联合抑制在癌细胞中的作用尚不清楚。在这里，我们确定了抑制PARP-1和不存在或RNAi敲低PARG对PAR合成、化疗后细胞死亡和长期生存力的影响。使用三个实验/临床PARP-1抑制剂在PARG无效细胞，我们显示PAR水平降低，并增加短期和长期的活力与每种抑制剂，DPQ除外。用实验化疗剂N-甲基-N '-硝基-N-亚硝基胍（MNNG）处理导致PARG缺失细胞中的细胞死亡增加，但用每种PARP-1抑制剂预处理时细胞死亡减少。在MNNG处理的HeLa细胞中观察到类似的结果，其中PARG的RNAi敲低或用ABT-888预处理导致HeLa细胞死亡增加，而PARG RNAi敲低+ ABT-888的组合未能产生细胞死亡增加。结果证明了在不存在PARG的情况下，PARP-1抑制剂在化学治疗后降低PAR水平、维持活力和减少PAR介导的细胞死亡的能力。此外，结果表明，在化疗中PARP-1和PARG抑制的组合不产生增加的HeLa细胞死亡。因此，结果表明，抑制PARP-1和PARG（两者都是增加癌细胞死亡的化疗靶标）不会导致HeLa细胞中的协同细胞死亡。因此，可能需要靶向PAR代谢以改善癌症治疗的策略来分别靶向PARP-1和PARG，以优化癌细胞死亡。
The genome-protecting role of poly(ADP-ribose) (PAR) has identified PAR polymerase-1 (PARP-1) and PAR glycohydrolase (PARG), two enzymes responsible for the synthesis and hydrolysis of PAR, as chemotherapeutic targets. Each has been previously individually evaluated in chemotherapy, but the effects of combination PARP-1 and PARG inhibition in cancer cells are not known. Here we determined the effects of the inhibition of PARP-1 and the absence or RNAi knockdown of PARG on PAR synthesis, cell death after chemotherapy and long-term viability. Using three experimental/clinical PARP-1 inhibitors in PARG-null cells, we show decreased levels of PAR and increased short-term and long-term viability with each inhibitor, with the exception of DPQ. Treatment with the experimental chemotherapeutic agent, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG), led to increased cell death in PARG-null cells, but decreased cell death when pretreated with each PARP-1 inhibitor. Similar results were observed in MNNG-treated HeLa cells, where RNAi knockdown of PARG or pretreatment with ABT-888 led to increased HeLa cell death, whereas combination PARG RNAi knockdown + ABT-888 failed to produce increased cell death. The results demonstrate the ability of the PARP-1 inhibitors to decrease PAR levels, maintain viability and decrease PAR-mediated cell death after chemotherapeutic treatment in the absence of PARG. Further, the results demonstrate that the combination of PARP-1 and PARG inhibition in chemotherapy does not produce increased HeLa cell death. Thus, the results indicate that inhibiting both PARP-1 and PARG, which both are chemotherapeutic targets that increase cancer cell death, does not lead to synergistic cell death in HeLa cells. Therefore, strategies that target PAR metabolism for the improved treatment of cancer may be required to target PARP-1 and PARG individually in order to optimize cancer cell death.
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影响因子：
4
作者：
Ame, Jean-Christophe;Fouquerel, Elise;Schreiber, Valerie
通讯作者：
Schreiber, Valerie
影响因子：
4.3
作者：
Fathers, Catherine;Drayton, Ross M.;Bryant, Helen E.
通讯作者：
Bryant, Helen E.
影响因子：
8.4
作者：
Kjellen, E;Pero, RW;Wennerberg, J
通讯作者：
Wennerberg, J
影响因子：
4.7
作者：
Min, WooKee;Cortes, Ulrich;Wang, Zhao-Qi
通讯作者：
Wang, Zhao-Qi
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.