Li Fengzhi
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo New York, USA.
Am J Cancer Res. 2014 May 26;4(3):304-11. eCollection 2014.
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.
能否找到一种解决方案，克服因各种癌症类型中不同的基因和表观遗传改变而导致的所有化疗和/或放疗耐药性？答案可能是否定的。然而，有两种方法可能有助于实现这一目标。一种方法是使用针对多种机制来杀死癌细胞的联合疗法，这是目前的先进方法。这种方法存在成本高和/或毒性限制的问题，因为每种药物的毒性往往具有累加性。尽管这种联合用药方法已被证明优于大多数目前的单一用药方法，但尚未被证明是一个重大成功。实现该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，在以生存素基因作为靶点和生物标志物进行抗癌药物的靶向发现过程中，偶然发现了一种小分子化学物质（FL118）。发现FL118不仅能抑制凋亡抑制蛋白（IAP）家族中的多种抗凋亡蛋白（生存素、XIAP、cIAP2），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，FL118对这些靶基因和肿瘤生长的抑制作用与p53状态（野生型、突变型或缺失型）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，FL118可能有效地控制失去功能性p53的癌症，而在这种癌症中，大多数（如果不是全部）DNA损伤药物显示出明显的低效性。最近的研究进一步表明，FL118卓越的抗癌活性高度依赖于其一级结构和空间构型，这表明FL118可能是一个有前景的药物平台，可基于其核心结构生成新型衍生物。有趣的是，尽管FL118与伊立替康和拓扑替康结构相似，这两种是美国食品药品监督管理局（FDA）批准用于癌症治疗的拓扑异构酶1（Top1）抑制剂，但具有Top1突变的癌细胞对FL118的抗肿瘤活性几乎没有产生耐药性，而对伊立替康和拓扑替康的耐药性却显著增加。此外，伊立替康和拓扑替康都是外排泵ABCG2的底物；高表达ABCG2的癌细胞对伊立替康和拓扑替康表现出很强的耐药性。相比之下，FL118不是ABCG2的底物；癌细胞中ABCG2的过表达对FL118治疗不显示耐药性。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FL118更多意想不到的作用机制。
