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细胞都有再循环不需要蛋白或受损蛋白的能力，分解后将它们重新用作"组装部件"。但是，癌细胞却扩大了这种称为“自噬”的系统，依靠它来逃避面对化疗和其他治疗的损伤。现在，研究人员已经开发出一种强效新药，可阻塞再循环系统，杀死模型小鼠的肿瘤细胞。 以前，有一种古老的抗疟疾药，名叫羟氯喹，可减弱癌细胞自噬，使癌细胞接触化疗药时尽可能地死亡。这一对策正在进行临床测试，初步结果是很有前景的。于是，研究人员设计了一系列氯喹类化合物，并进行相关研究，从中发现一种高效的新化合物Lys05。在这周的Proceedings of the National Academy of Sciences上，研究人员对Lys05的设计、化学合成及生物学评价进行了详细报道。 Lys05与羟氯喹不一样，羟氯喹单独使用时对肿瘤细胞几乎没有影响，而Lys05甚至在没有其他抗肿瘤治疗法存在下也可减缓模型动物的肿瘤生长，更重要的是，此时的Lys05剂量对癌细胞是有毒的，对健康细胞影响很小或没有影响，因为这是一种再循环上瘾的剂量，癌细胞比健康细胞更依赖于它。 对动物来说，Lys05抗肿瘤活性的剂量是无毒的，这表明，这种药物或其衍生物可能比羟氯喹更有效。然而，值得注意的是，当研究人员增加Lys05剂量时，一些动物形成模仿自噬基因ATG16L1已知遗传缺陷的症状，其中此遗传缺陷会影响一些克罗恩病患者。这种术称拟表型（表型模拟）的相似性清楚地表明，lys05通过干扰细胞再循环系统起作用。Lys05及其配对物Lys01还没有完全准备好进行临床测试，在此之前，还需要优化分子，进行更多的动物毒性测试。同时，这一研究说明了自噬对于癌细胞相当重要，向未来疗法迈近了重要的一步。（生物谷bioon.com） Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency Q. McAfee, Z. Zhang, A. Samanta, S. M. Levi, X.-H. Ma, S. Piao, J. P. Lynch, T. Uehara, A. R. Sepulveda, L. E. Davis, J. D. Winkler, R. K. Amaravadi Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer |
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