Targeting the Achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance.
Targeting the Achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance.
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DOI：
10.1021/cr4006236
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发表时间：
2014-06-11
期刊：
影响因子：
62.1
通讯作者：
Di Pietro, Attilio
中科院分区：
文献类型：
--
作者：
Szakacs, Gergely;Hall, Matthew D.;Gottesman, Michael M.;Boumendjel, Ahcene;Kachadourian, Remy;Day, Brian J.;Baubichon-Cortay, Helene;Di Pietro, Attilio
癌症患者多药耐药性 (MDR) 的发展仍然是一个重大的临床挑战，其中 ABC（ATP 结合盒）转运蛋白的药物外流发挥着重要作用。避免这些多特异性外排转运蛋白导致的药物积累减少的策略依赖于尝试开发绕过挤出的药物（通常会牺牲活性）或探索临床抑制剂，尽管在体外显示出希望，但尚未转化为临床。在癌细胞进化过程中赋予选择性优势的改变也可能产生可用于治疗的脆弱性。 1 根据 Szybalski 和 Bryson 的定义，附带敏感性是“在大多数体外研究中发现的耐药细胞（原核或真核）中的一种现象……[由此]细胞对一种药物产生耐药性可以赋予对替代药物比原始（亲本）细胞系更高的敏感性”。 2 换句话说，耐药细胞系比其来源的亲本细胞系对细胞毒素更敏感（图 1）。从这个角度来看，耐药性可以解释为新药可以针对的一种特征。在这篇综述中，我们讨论了附带敏感性的一般机制，并重点关注据报道可在过度表达三种主要多药转运蛋白之一的细胞中引起毒性增加的小分子。此类分子（称为 MDR 选择性化合物）以多重耐药循环细胞为目标，这表明 MDR ABC 转运蛋白可被视为最终的“阿喀琉斯之踵”——致命地伤害多重耐药癌细胞的微妙部位。在此，我们讨论了这项新兴技术的潜力，对文献中报道的 MDR 选择性化合物进行了分类，并强调了与 MDR 选择性毒性相关的化学特征。
The development of multidrug resistance (MDR) in patients suffering cancer remains a significant clinical challenge, with drug efflux by ABC (ATP-binding cassette) transporters contributing significantly. Strategies to circumvent the reduced drug accumulation conferred by these polyspecific efflux transporters have relied on attempts to develop drugs that bypass extrusion (often with a sacrifice in activity) or the exploration of clinical inhibitors that, although showing promise in vitro, have not translated to the clinic. Alterations that confer selective advantage during the evolution of cancer cells might also create vulnerabilities that can be exploited therapeutically. 1 As defined by Szybalski and Bryson, collateral sensitivity is a “phenomenon in drug-resistant cells (prokaryotic or eukaryotic) identified during most in vitro studies...[whereby] the development of resistance in cells to one agent can confer higher sensitivity to an alternate agent than seen in the original (parental) line”. 2 In other words, the resistant cell line is more sensitive to a cytotoxin than the parental line from which it is derived (Figure 1). From this perspective, resistance can be interpreted as a trait that could be targeted by new drugs. In this review, we discuss general mechanisms underlying collateral sensitivity and focus on small molecules reported to elicit increased toxicity in cells overexpressing one of the three major multidrug transporters. Such molecules (termed MDR-selective compounds) target multidrug-resistant cycling cells, suggesting that MDR ABC transporters could be considered as the ultimate “Achilles’ heel” the exquisite spot to fatally wound a multidrug-resistant cancer cell. Herein, we discuss the potential of this emerging technology, cataloging MDR-selective compounds reported in the literature and highlighting chemical features that are associated with MDR-selective toxicity.
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影响因子：
8.4
作者：
Anderson, CP;Tsai, J;Reynolds, CP
通讯作者：
Reynolds, CP
影响因子：
2.9
作者：
Bhatia, A;Schäfer, HJ;Hrycyna, CA
通讯作者：
Hrycyna, CA
MDR和非MDR细胞中对pluron子的差异代谢反应：耐药性癌症化学敏化的新途径。
影响因子：
10.8
作者：
Alakhova, Daria Yu.;Rapoport, Nataliya Y.;Batrakova, Elena V.;Timoshin, Alexander A.;Li, Shu;Nicholls, David;Alakhov, Valery Yu.;Kabanov, Alexander V.
通讯作者：
Kabanov, Alexander V.
影响因子：
3.8
作者：
Brechbuhl HM;Kachadourian R;Min E;Chan D;Day BJ
通讯作者：
Day BJ
影响因子：
8.8
作者：
Batrakova EV;Li S;Elmquist WF;Miller DW;Alakhov VY;Kabanov AV
通讯作者：
Kabanov AV