GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma
GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma
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DOI：
10.1007/s10637-019-00741-3
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发表时间：
2019-12-01
影响因子：
3.4
通讯作者：
Halfon, Philipe
中科院分区：
文献类型：
--
作者：
Brun, Sonia;Bassissi, Firas;Halfon, Philipe
在肿瘤细胞的获得性修饰中，溶酶体表型和功能的变化得到了很好的描述，使溶酶体成为新疗法的潜在靶点。一些弱碱性亲脂性药物对溶酶体有特殊的亲和力，利用溶酶体捕获的优势发挥抗癌活性。在这里，我们开发了一种新的溶酶体致性小分子GNS561，并在多种体外肝内胆管癌细胞模型(HuCCT1和RBE细胞系以及患者来源的细胞)和鸡绒毛膜尿囊膜异种移植模型中评价了它的活性。GNS561显著降低两种肝内胆管癌细胞系(HuCCT1的IC50为1.5+/-0.2mU和RBE细胞的IC50为1.7+/-0.1mU)的存活率，并通过半胱氨酸天冬氨酸氨基转移酶(Caspase)活性检测诱导细胞凋亡。我们证实了GNS561介导的细胞死亡与其溶酶体亲和性有关。GNS561诱导溶酶体失调，这是通过抑制晚期自噬和诱导剂量依赖的扩大的溶酶体积聚来证实的。在患者来源的细胞模型中，GNS561分别在2/5和1/5的患者来源细胞模型中比顺铂和吉西他滨更有效。此外，在这些模型中，GNS561在对吉西他滨敏感性较低的模型中有效。在鸡绒毛膜尿囊膜异种移植模型中，GNS561对人肝内胆管癌细胞株也有有效的体内抑制作用，在该模型中具有良好的耐受性，足以诱导抗肿瘤作用。综上所述，GNS561是一种新型溶酶体促进剂，对肝内胆管癌细胞具有抗癌活性。目前正在进行进一步的调查，以充分阐明其作用机制。
Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC50 of 1.5 +/- 0.2 mu M in HuCCT1 and IC50 of 1.7 +/- 0.1 mu M in RBE cells) and induced apoptosis as measured by caspases activation. We confirmed that GNS561-mediated cell death was related to its lysosomotropic properties. GNS561 induced lysosomal dysregulation as proven by inhibition of late-stage autophagy and induction of a dose-dependent build-up of enlarged lysosomes. In patient-derived cells, GNS561 was more potent than cisplatin and gemcitabine in 2/5 and 1/5 of the patient-derived cells models, respectively. Moreover, in these models, GNS561 was potent in models with low sensitivity to gemcitabine. GNS561 was also efficient in vivo against a human intrahepatic cholangiocarcinoma cell line in a chicken chorioallantoic membrane xenograft model, with a good tolerance at doses high enough to induce an antitumor effect in this model. In summary, GNS561 is a new lysosomotropic agent, with an anticancer activity against intrahepatic cholangiocarcinoma. Further investigations are currently ongoing to fully elucidate its mechanism of action.