Context-Dependent Antagonism between Akt Inhibitors and Topoisomerase Poisons
Context-Dependent Antagonism between Akt Inhibitors and Topoisomerase Poisons
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DOI：
10.1124/mol.113.088674
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发表时间：
2014-05-01
影响因子：
3.6
通讯作者：
Kaufmann, Scott H.
中科院分区：
文献类型：
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作者：
Galvez-Peralta, Marina;Flatten, Karen S.;Kaufmann, Scott H.
通过磷脂酰肌醇-3激酶（PI 3 K）/Akt途径的信号传导（其在>50%的癌中被异常激活）抑制细胞凋亡并促成耐药性。因此，几种Akt抑制剂目前正在进行临床前或早期临床测试。为了检测Akt抑制对多种广泛使用的抗肿瘤剂的活性的影响，将人癌细胞系用Akt抑制剂A-443654 [（2S）-1-（2S（1H-吲哚-3-基）-3-[5-（2-甲氧基苯基）-2-（三氟甲基）苯基]-2-甲基-IH-吲哚-3-基（3-甲基-2H-吲唑-5-基）吡啶-3-基]氧基丙-2-胺; ATP竞争性]或MK-2206（8-[4-（1-氨基环丁基）苯基]-9-苯基-2H-[1，2，4]三唑并[3，4-f][1，6]萘啶-3-酮;二盐酸盐;变构抑制剂）或用靶向磷酸肌醇依赖性激酶1（PDK 1）的小干扰RNA（siRNA）沿着顺铂、美法仑、喜树碱或依托泊苷，并测定集落形成。当Akt抑制剂与不同药物组合时，观察到令人惊讶的不同结果。当A-443654或MK-2206与DNA交联剂顺铂或美法仑联合使用时，在多个细胞系中观察到协同效应，与PI 3 K通路状态无关。相比之下，Akt抑制剂与喜树碱或依托泊苷组合的作用更复杂。在HCT 116和DLD 1细胞中，含有活化PI 3 KCA突变，在宽浓度范围内，A-443654增强了喜树碱或依托泊苷的作用。相反，在缺乏活化PI 3 KCA突变的细胞系中，Akt信号传导的部分抑制与喜树碱或依托泊苷协同作用，但较高浓度的A-443654或MK-2206（>80% Akt信号传导抑制）或PDK 1 siRNA通过减少DNA合成拮抗拓扑异构酶毒物，这一过程有助于这些药物的有效DNA损伤和杀伤。这些结果表明，PI 3 K/Akt通路的抑制剂与某些类别的化疗剂组合的效果可能比以前认识到的更复杂。
Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl] oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl) phenyl]-9-phenyl-2H-[1,2,4] triazolo[3,4-f][1,6] naphthyridin-3-one; dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more complicated than previously recognized.