Anticancer drug FL118 is more than a survivin inhibitor: where is the Achilles' heel of cancer?
Anticancer drug FL118 is more than a survivin inhibitor: where is the Achilles' heel of cancer?
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发表时间：
2014-05
影响因子：
5.3
通讯作者：
Fengzhi Li
中科院分区：
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作者：
Fengzhi Li
能否找到一种解决方案，克服各种癌症类型中不同遗传和表观遗传变异导致的所有化疗和/或放疗抗性？答案可能是否定的。然而，有两种方法可以达到这个目标。一种方法是通过使用针对多种机制杀死癌细胞的综合疗法，这是当前的最新技术水平。这种方法提出了成本高和/或毒性限制的问题，因为每种药物的毒性通常是相加的。这种多药治疗方法尚未被证明是一个重大的成功，虽然它已被证明是上级最目前的单一药物治疗方法。实现这一目标的另一种方法是找到一种针对多种不同治疗耐药机制的单一抗癌药物。在这方面，最近在使用生存素基因作为靶标和生物标志物的抗癌药物的靶向发现过程中偶然发现了一种小化学分子（FL 118）。FL 118不仅能抑制凋亡抑制因子（IAP）家族中的多种抗凋亡蛋白（survivin、XIAP、cIAP 2），还能抑制Bcl-2家族中的抗凋亡蛋白Mcl-1，同时诱导促凋亡蛋白Bax和Bim的表达。重要的是，FL 118对这些靶基因和肿瘤生长的抑制与p53状态（野生型、突变型或无效）无关，尽管在具有不同p53状态的细胞中作用机制可能不同。因此，FL 118可以有效地控制失去功能性p53的癌症，其中大多数DNA损伤药物（如果不是全部的话）显示出明显缺乏效率。最近的研究进一步揭示了FL 118的上级抗癌活性高度依赖于其一级结构和空间构型，这表明FL 118可能是基于其核心结构产生新型衍生物的有前途的药物平台。有趣的是，尽管FL 118与伊立替康和拓扑替康（两种FDA批准的用于癌症治疗的拓扑异构酶1（Top1）抑制剂）具有结构相似性，但具有Top1突变的癌细胞对FL 118抗肿瘤活性的治疗抗性贡献很小，同时显著增加伊立替康和拓扑替康抗性。此外，伊立替康和拓扑替康都是外排泵ABCG 2底物; ABCG 2高表达的癌细胞显示出强的伊立替康和拓扑替康耐药。相反，FL 118不是ABCG 2底物;癌细胞中ABCG 2过表达不显示对FL 118治疗的抗性。目前的证据表明，未来的研究可能会揭示这种独特的小分子FL 118的更多意想不到的作用机制。
Can a solution be found that overcomes all chemotherapy and/or radiation resistance resulting from different genetic and epigenetic alternations in various cancer types? The answer is likely NO. However, there are two ways that may be followed to approach this goal. One way is through the use of poly-therapies that target multiple mechanisms to kill cancer cells, which is the current state of the art. This approach raises issues of high costs and/or toxic limitations, since the toxicities of each agent are often additive. This poly-pharmacy approach has not proven to be a major success, although it has proven to be superior to most current mono-pharmacy approaches. The other way to approach the goal is to find a single anticancer drug that targets multiple different treatment resistant mechanisms. In this regard, a small chemical molecule (FL118) was recently discovered by serendipity during targeted discovery of anticancer drugs using the survivin gene as a target and biomarker. FL118 was found to not only inhibit multiple antiapoptotic proteins (survivin, XIAP, cIAP2) in the inhibitor of apoptosis (IAP) family, but to also inhibit the antiapoptotic protein Mcl-1 in the Bcl-2 family, while inducing the pro-apoptotic proteins Bax and Bim expression. Importantly, inhibition of these target genes and of tumor growth by FL118 is independent of p53 status (wild type, mutant or null), although mechanisms of action may be distinct among cells with different p53 status. Therefore, FL118 may effectively control cancer that loses functional p53, in which most DNA damage drugs (if not all) show a marked lack of efficiency. Recent studies further revealed that the superior anticancer activity of FL118 is highly dependent on its primary structure and steric configuration, suggesting that FL118 may be a promising drug platform for generating novel derivatives based on its core structure. Intriguingly, although FL118 has structural similarity to irinotecan and topotecan, two FDA-approved topoisomerase 1 (Top1) inhibitors for cancer treatment, cancer cells with Top1 mutations shows little contributions of treatment resistance to FL118 antitumor activity, while strikingly increasing irinotecan and topotecan resistance. Furthermore, both irinotecan and topotecan are the efflux pump ABCG2 substrates; cancer cells with high expression of ABCG2 showed strong irinotecan and topotecan resistance. In contrast, FL118 is not an ABCG2 substrate; ABCG2 overexpression in cancer cells does not show resistance to FL118 treatment. Current evidence suggests that future studies may unravel more unexpected mechanisms of action for this unique small molecule FL118.