Multidrug Efflux Pumps Attenuate the Effect of MGMT Inhibitors.
Multidrug Efflux Pumps Attenuate the Effect of MGMT Inhibitors.
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多药外排泵减弱 MGMT 抑制剂的作用
DOI：
10.1021/acs.molpharmaceut.5b00341
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发表时间：
2015
影响因子：
4.9
通讯作者：
Kaina B
中科院分区：
文献类型：
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作者：
Tomaszowski KH;Schirrmacher R;Kaina B
耐药性的各种机制削弱了癌症治疗的有效性，包括药物转运和DNA修复。DNA修复蛋白O 6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是决定细胞对烷化剂类抗癌药物耐药的关键因素，而MGMT的失活或缺失使细胞对甲基化和氯乙基化药物更敏感。设计了高度特异和有效的修复蛋白MGMT抑制剂，包括O 6-苄基鸟嘌呤（O 6-benzylguanine，O 6-BG）和O 6-（4-bromothenyl）guanine（O 6-BTG），它们本身是无毒的。不幸的是，这些抑制剂不能在正常细胞和癌细胞中的MGMT之间进行选择，从而在健康组织中引起非靶向效应。因此，需要MGMT抑制剂的靶向策略。在这里，我们使用与β-d-葡萄糖缀合的O 6 BG和O 6 BTG（分别为O 6 BG-Glu和O 6 BTG-Glu）来选择性地抑制肿瘤中的MGMT，利用它们对葡萄糖的高需求。两种葡萄糖缀合物在几种癌细胞系中有效抑制MGMT，但对DNA烷化剂的致敏程度不同，洛莫司汀比替莫唑胺更有效。我们进一步表明，葡萄糖结合物受到ATP结合盒（ABC）转运蛋白介导的外排，涉及P-糖蛋白，MRP 1和BCRP，这影响了MGMT抑制的效率。令人惊讶的是，O 6 BG和O 6 BTG也经历主动转运出细胞。我们还表明，外排转运蛋白的药理学抑制增加了这些MGMT抑制剂和替莫唑胺治疗后细胞死亡的诱导。我们的结论是，要实现成功的MGMT靶向，需要采取减弱ABC转运蛋白外排的策略。
Various mechanisms of drug resistance attenuate the effectiveness of cancer therapeutics, including drug transport and DNA repair. The DNA repair proteinO6-methylguanine-DNA methyltransferase (MGMT) is a key factor determining the resistance against alkylating anticancer drugs inducing the genotoxic DNA lesionsO6-methylguanine andO6-chloroethylguanine, and MGMT inactivation or depletion renders cells more susceptible to treatment with methylating and chloroethylating agents. Highly specific and efficient inhibitors of the repair protein MGMT were designed, includingO6-benzylguanine (O6BG) andO6-(4-bromothenyl)guanine (O6BTG) that are nontoxic on their own. Unfortunately, these inhibitors do not select between MGMT in normal and cancer cells, causing nontarget effects in the healthy tissue. Therefore, a targeting strategy for MGMT inhibitors is required. Here, we used O6BG and O6BTG conjugated to β-d-glucose (O6BG-Glu and O6BTG-Glu, respectively) in order to selectively inhibit MGMT in tumors, harnessing their high demand for glucose. Both glucose conjugates efficiently inhibited MGMT in several cancer cell lines, but with different extents of sensitization to DNA alkylating agents, with lomustine being more effective than temozolomide. We further show that the glucose conjugates are subject to ATP-binding cassette (ABC) transporter mediated efflux, involving P-glycoprotein, MRP1, and BCRP, which impacts the efficiency of MGMT inhibition. Surprisingly, also O6BG and O6BTG were subject to an active transport out of the cell. We also show that pharmacological inhibition of efflux transporters increases the induction of cell death following treatment with these MGMT inhibitors and temozolomide. We conclude that strategies of attenuating the efflux by ABC transporters are required for achieving successful MGMT targeting.
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DNA 修复对突变非线性剂量反应的影响
影响因子：
3.8
作者：
Adam D. Thomas;G. Jenkins;B. Kaina;O. Bodger;Karl;P. Lewis;S. Doak;G. Johnson
通讯作者：
G. Johnson
使用双链和缺口质粒比较大肠杆菌中 O6-甲基-、O6-乙基鸟嘌呤和 O4-甲基胸腺嘧啶的诱变。
影响因子：
4.7
作者：
G. Pauly;Stephen H. Hughes;R. Moschel
通讯作者：
R. Moschel
影响因子：
4.1
作者：
Pegg AE
通讯作者：
Pegg AE
O6-苄基鸟嘌呤的代谢，O6-烷基鸟嘌呤-DNA 烷基转移酶的灭活剂。
影响因子：
11.2
作者：
Dolan,ME;Chae,MY;Pegg,AE;Mullen,JH;Friedman,HS;Moschel,RC
通讯作者：
Moschel,RC
A.Honda 等人：“流感病毒转录和复制的最小分子结构”Proc。
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