細(xì)胞都有再循環(huán)不需要蛋白或受損蛋白的能力,，分解后將它們重新用作"組裝部件"。但是,，癌細(xì)胞卻擴(kuò)大了這種稱為“自噬”的系統(tǒng),，依靠它來逃避面對化療和其他治療的損傷。現(xiàn)在,，研究人員已經(jīng)開發(fā)出一種強(qiáng)效新藥,，可阻塞再循環(huán)系統(tǒng),，殺死模型小鼠的腫瘤細(xì)胞,。
以前,，有一種古老的抗瘧疾藥，名叫羥氯喹,，可減弱癌細(xì)胞自噬,，使癌細(xì)胞接觸化療藥時(shí)盡可能地死亡。這一對策正在進(jìn)行臨床測試,，初步結(jié)果是很有前景的,。于是，研究人員設(shè)計(jì)了一系列氯喹類化合物,，并進(jìn)行相關(guān)研究,，從中發(fā)現(xiàn)一種高效的新化合物L(fēng)ys05。在這周的Proceedings of the National Academy of Sciences上,，研究人員對Lys05的設(shè)計(jì),、化學(xué)合成及生物學(xué)評價(jià)進(jìn)行了詳細(xì)報(bào)道。
Lys05與羥氯喹不一樣,，羥氯喹單獨(dú)使用時(shí)對腫瘤細(xì)胞幾乎沒有影響,，而Lys05甚至在沒有其他抗腫瘤治療法存在下也可減緩模型動(dòng)物的腫瘤生長，更重要的是,，此時(shí)的Lys05劑量對癌細(xì)胞是有毒的,，對健康細(xì)胞影響很小或沒有影響，因?yàn)檫@是一種再循環(huán)上癮的劑量,，癌細(xì)胞比健康細(xì)胞更依賴于它,。
對動(dòng)物來說，Lys05抗腫瘤活性的劑量是無毒的,，這表明,，這種藥物或其衍生物可能比羥氯喹更有效。然而,，值得注意的是,，當(dāng)研究人員增加Lys05劑量時(shí)，一些動(dòng)物形成模仿自噬基因ATG16L1已知遺傳缺陷的癥狀,，其中此遺傳缺陷會(huì)影響一些克羅恩病患者,。這種術(shù)稱擬表型（表型模擬）的相似性清楚地表明，lys05通過干擾細(xì)胞再循環(huán)系統(tǒng)起作用,。Lys05及其配對物L(fēng)ys01還沒有完全準(zhǔn)備好進(jìn)行臨床測試,，在此之前，還需要優(yōu)化分子,，進(jìn)行更多的動(dòng)物毒性測試,。同時(shí),，這一研究說明了自噬對于癌細(xì)胞相當(dāng)重要，向未來療法邁近了重要的一步,。（生物谷bioon.com）
doi:10.1073/pnas.1118193109
PMC:
PMID:
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.
