Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone.
Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone.
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发表时间：
2004-07
影响因子：
2
通讯作者：
M. Luo;M. Kelley
中科院分区：
文献类型：
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作者：
M. Luo;M. Kelley
细胞通过四种主要机制修复DNA损伤，然而，由烷化剂和氧化损伤诱导的损伤主要通过DNA碱基切除修复（BER）途径修复。AP内切核酸酶APE 1是BER途径中的主要酶之一。它在人类细胞中含量丰富，并且几乎解释了在细胞提取物中观察到的所有脱碱基位点切割活性。APE 1表达在多种癌症中升高，并且APE 1高表达与放化疗的不良结果相关。研究表明，小分子荧光素酮能增强电离辐射对细胞的杀伤能力，初步证据表明，荧光素酮可能抑制AP核酸内切酶。考虑到APE 1在修复氧化和电离辐射DNA损伤中的作用，以及关于Lucanthone作为电离辐射增强剂的报道和Lucanthone作为AP核酸内切酶抑制剂的潜在用途，我们研究了Lucanthone是否可以抑制APE 1核酸内切酶活性。我们报告说，lucanthone抑制APE 1的修复活性，但不抑制其氧化还原功能或核酸外切酶对错配核苷酸的活性。Lucanthone似乎还抑制核酸外切酶III家族成员（APE 1和Exo III），但不抑制核酸内切酶IV AP核酸内切酶，也不抑制双功能糖基化酶/裂解酶，如核酸内切酶VIII或甲酰氨基嘧啶-DNA糖基化酶（Fpg）。此外，添加紫锥菊酮抑制细胞提取物的APE 1修复活性，并增强实验室烷化剂甲磺酸甲酯（MMS）和临床相关试剂替莫唑胺（TMZ）的细胞杀伤作用。鉴于这些初步的研究结果，这将是感兴趣的进一步开发作为APE 1抑制剂，通过使用的结构-功能研究作为一种手段，增强肿瘤化疗药物的敏感性。
Cells repair DNA damage via four main mechanisms, however, damage induced by alkylators and oxidative damage is predominantly repaired by the DNA base excision repair (BER) pathway. The AP endonuclease, APE1, is one of the main enzymes in the BER pathway. It is abundant in human cells and accounts for nearly all of the abasic site cleavage activity observed in cellular extracts. APE1 expression is elevated in a variety of cancers and a high APE1 expression has been associated with poor outcome to chemoradiotherapy. The small molecule lucanthone has been shown to enhance the killing ability of ionizing radiation in cells and preliminary evidence suggests that lucanthone may inhibit AP endonuclease. Given the role APE1 plays in repairing oxidative and ionizing radiation DNA damage, the reports of lucanthone as an ionizing radiation enhancer and the potential use of lucanthone as an AP endonuclease inhibitor, we examined whether lucanthone could inhibit APE1 endonuclease activity. We report that lucanthone inhibits the repair activity of APE1, but not its redox function or exonuclease activity on mismatched nucleotides. Lucanthone also appears to inhibit exonuclease III family members (APE1 and ExoIII), but not endonuclease IV AP endonucleases, nor bifunctional glycosylase/lyases such as endonuclease VIII or formamidopyrimidine-DNA glycosylase (Fpg). Furthermore, the addition of lucanthone inhibits APE1 repair activity from cellular extracts and enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate (MMS) and the clinically relevant agent temozolomide (TMZ). Given these initial findings, it would be of interest to further develop lucanthone as an APE1 inhibitor through the use of structure-function studies as a means of enhancing the sensitization of tumors to chemotherapeutic agents.