DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer.
DNA polymerase β as a novel target for chemotherapeutic intervention of colorectal cancer.
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DOI：
10.1371/journal.pone.0016691
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发表时间：
2011-02-02
期刊：
影响因子：
3.7
通讯作者：
Narayan S
中科院分区：
文献类型：
--
作者：
Jaiswal AS;Banerjee S;Aneja R;Sarkar FH;Ostrov DA;Narayan S
化学预防是结直肠癌医疗管理的主要策略。大多数用于治疗结直肠癌的药物都会引起DNA烷基化损伤，这种损伤主要通过碱基切除修复(BER)途径来修复。因此，阻断BER通路是抑制结直肠癌扩散的一个有吸引力的选择。使用电子计算机方法，我们通过将小分子对接到DNA聚合酶β(POL-β)上进行了基于结构的筛选，并确定了一种有效的抗POL-β化合物，NSC-124854。我们的目标是研究NSC-124854是否可以通过阻断BER来增强DNA烷化剂替莫唑胺的治疗效果。首先，我们通过检测APE1、FEN1、β连接酶I以及POL-β导向的单核苷酸(SN)和长补丁(LP)-BER的体外活性来确定NSC-124854对POL-BER的特异性。其次，我们利用体外克隆形成实验研究了NSC-124854对曲美他滨抑制错配修复缺陷和错配修复熟练的结肠癌细胞株生长的影响。第三，我们探讨了NSC-124854对TMZ诱导的移植到雌性纯合SCID小鼠体内的肿瘤生长的抑制作用。我们的数据表明，在体外重组系统中，NSC-124854对POL-β具有高度的特异性，并阻断了POL-β介导的SN和LP-BER活性。此外，在体外细胞培养和体内异种移植模型中，NSC-124854都有效地诱导了TMZ对MMR缺乏和MMR熟练的结肠癌细胞的敏感性。我们的发现提示了一种潜在的新策略，用于开发高度特异的基于结构的抑制物来防止结肠肿瘤的进展。
Chemoprevention presents a major strategy for the medical management of colorectal cancer. Most drugs used for colorectal cancer therapy induce DNA-alkylation damage, which is primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Using an in silico approach, we performed a structure-based screen by docking small-molecules onto DNA polymerase β (Pol-β) and identified a potent anti-Pol-β compound, NSC-124854. Our goal was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA-alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-β by examining in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we investigated the effect of NSC-124854 on the efficacy of TMZ to inhibit the growth of mismatch repair (MMR)-deficient and MMR-proficient colon cancer cell lines using in vitro clonogenic assays. Third, we explored the effect of NSC-124854 on TMZ-induced in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic xenografts implanted in female homozygous SCID mice. Our data showed that NSC-124854 has high specificity to Pol-β and blocked Pol-β-directed SN- and LP-BER activities in in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR-proficient colon cancer cells both in vitro cell culture and in vivo xenograft models. Our findings suggest a potential novel strategy for the development of highly specific structure-based inhibitor for the prevention of colonic tumor progression.
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影响因子：
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作者：
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影响因子：
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腺瘤性息肉大肠杆菌（APC）在调节DNA修复中的新功能。
影响因子：
9.7
作者：
Jaiswal, Aruna S.;Narayan, Satya
通讯作者：
Narayan, Satya