Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides.
Effects of gemcitabine on APE/ref-1 endonuclease activity in pancreatic cancer cells, and the therapeutic potential of antisense oligonucleotides.
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DOI：
10.1038/sj.bjc.6602080
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发表时间：
2004-09-13
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
脱氧核糖核酸内切酶(APE)是DNA碱基切除修复(BER)过程中的一个关键酶，常在人类癌症中高水平表达。核苷类似物吉西他滨(2‘，2’-二氟-2‘-脱氧胞苷)处理的胰腺癌细胞显示APE/氧化还原效应因子(REF-1)蛋白水平增加(PANC-1约为PANC-1的两倍，MiaPaCa-2约为MIaPaCa-2的6倍)，核酸内切酶活性也相应增加。这些结果表明，APE/REF-1的激活可能是一种适应性反应，通过促进BER而导致吉西他滨耐药。为了验证这一假设，我们检查了使用反义干扰APE/REF-1对吉西他滨毒性的影响。与对照组相比，反义寡核苷酸使MiaPaCa-2和PANC-1的蛋白质水平分别降低了三倍和五倍，与核酸内切酶活性降低有关。反义寡核苷酸和吉西他滨的联合治疗部分抑制了单独暴露于吉西他滨的细胞中APE/REF-1活性的增加。克隆形成实验显示，反义寡核苷酸或吉西他滨单独处理的细胞集落形成率仅略有下降，但与APE/REF-1反义寡核苷酸联合使用后，吉西他滨对PANC-1细胞的毒性增加了2倍。总体而言，这些发现表明APE/REF-1在某些胰腺癌细胞对吉西他滨的耐药性中起着重要作用，并支持针对该蛋白的新疗法的进一步研究。
Apurinic/apyrimidinic endonuclease (APE) is a key enzyme involved in DNA base excision repair (BER) that is often expressed at elevated levels in human cancers. Pancreatic cancer cells treated with the nucleoside analogue gemcitabine (2′, 2′-difluoro-2′deoxycytidine) showed increases in APE/redox effector factor (ref-1) protein levels (approximately two-fold for Panc-1 and six-fold for MiaPaCa-2), with corresponding increases in endonuclease activity. These results suggested that the activation of APE/ref-1 might be an adaptive response that contributes to gemcitabine resistance by facilitating BER. To test this hypothesis, we examined the effects of disrupting APE/ref-1 using antisense on gemcitabine toxicity. Antisense oligonucleotides decreased protein levels three-fold in MiaPaCa-2 and five-fold in Panc-1 in comparison to controls, associated with reduced endonuclease activity. Combination treatments with antisense oligonucleotides and gemcitabine partially suppressed the increase in APE/ref-1 activity seen in cells exposed to gemcitabine alone. While clonogenic assays showed only slight decreases in colony formation in cells treated with either antisense oligonucleotides or gemcitabine alone, the combination with APE/ref-1 antisense resulted in a 2-log enhancement of gemcitabine toxicity in Panc-1 cells. Overall these findings suggest that APE/ref-1 plays a significant role in gemcitabine resistance in some pancreatic cancer cells, and support the further investigation of novel treatments that target this protein.
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影响因子：
11.4
作者：
Ema, M;Hirota, K;Fujii-Kuriyama, Y
通讯作者：
Fujii-Kuriyama, Y
DOI：
10.1016/s0360-3016(03)00448-6
发表时间：
2003-01-01
影响因子：
7
作者：
Haller, DG
通讯作者：
Haller, DG
DOI：
10.1073/pnas.93.17.8919
发表时间：
1996-08-20
影响因子：
11.1
作者：
Xanthoudakis, S;Smeyne, RJ;Curran, T
通讯作者：
Curran, T
影响因子：
15.9
作者：
Baldwin, AS
通讯作者：
Baldwin, AS
DOI：
10.1016/s0921-8777(98)00039-1
发表时间：
1998-10-21
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Ludwig, DL;MacInnes, MA;Chen, DJ
通讯作者：
Chen, DJ