The University of Vermont Cancer Center, Burlington, Vermont.
Department of Medicine, The University of Vermont, Burlington, Vermont.
J Cell Biochem. 2018 Jul;119(7):5921-5933. doi: 10.1002/jcb.26787. Epub 2018 Mar 25.
Autophagy has emerged as a mechanism critical to both tumorigenesis and development of resistance to multiple lines of anti-cancer therapy. Therefore, targeting autophagy and alternative cell death pathways has arisen as a viable strategy for refractory tumors. The anti-malarial 4-aminoquinoline compounds chloroquine and hydroxychloroquine are currently being considered for re-purposing as anti-cancer therapies intended to sensitize different tumors by targeting the lysosomal cell death pathway. Here, we describe a novel organometallic chloroquine derivative, cymanquine, that exhibits enhanced bioactivity compared to chloroquine in both normal, and reduced pH tumor microenvironments, thus overcoming a defined limitation of traditional 4-aminoquinolines. In vitro, cymanquine exhibits greater potency than CQ in a diverse panel of human cancer cell lines, including melanoma, in both normal pH and in reduced pH conditions that mimic the tumor microenvironment. Cymanquine treatment results in greater lysosomal accumulation than chloroquine and induces lysosomal dysfunction leading to autophagy blockade. Using a mouse model of vemurafenib-resistant melanoma, cymanquine slowed tumor growth greater than hydroxychloroquine, and when used in combination with vemurafenib, cymanquine partially restored sensitivity to vemurafenib. Overall, we show that cymanquine exhibits superior lysosomal accumulation and autophagy blockade than either chloroquine or hydroxychloroquine in vitro; and in addition to its high level of tolerability in mice, exhibits superior in vivo efficacy in a model of human melanoma.
自噬已成为肿瘤发生和对多种抗癌治疗耐药性发展的关键机制。因此，靶向自噬和替代细胞死亡途径已成为治疗难治性肿瘤的可行策略。抗疟 4-氨基喹啉化合物氯喹和羟氯喹目前正在被重新考虑用于癌症治疗，旨在通过靶向溶酶体细胞死亡途径来增敏不同的肿瘤。在这里，我们描述了一种新型的有机金属氯喹衍生物，即 cymanquine，与氯喹相比，它在正常和降低 pH 的肿瘤微环境中均表现出增强的生物活性，从而克服了传统 4-氨基喹啉的一个明确局限性。在体外，cymanquine 在包括黑色素瘤在内的多种人类癌细胞系中比 CQ 具有更强的效力，无论是在正常 pH 条件下还是在模拟肿瘤微环境的降低 pH 条件下。cymanquine 处理导致比氯喹更多的溶酶体积累，并诱导溶酶体功能障碍导致自噬阻断。使用维莫非尼耐药黑色素瘤的小鼠模型，cymanquine 减缓肿瘤生长的效果优于羟氯喹，并且当与维莫非尼联合使用时，cymanquine 部分恢复了对维莫非尼的敏感性。总的来说，我们表明 cymanquine 在体外比氯喹或羟氯喹具有更高的溶酶体积累和自噬阻断作用；除了在小鼠中具有高耐受性外，在人类黑色素瘤模型中还表现出优越的体内疗效。
