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Therefore, targeting autophagy and alternative cell death pathways has arisen as a viable strategy for refractory tumors. The anti\u2010malarial 4\u2010aminoquinoline compounds chloroquine and hydroxychloroquine are currently being considered for re\u2010purposing as anti\u2010cancer 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\u2010aminoquinolines. 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\u2010resistant 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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcb.26787","type":"journal-article","created":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T17:27:21Z","timestamp":1521998841000},"page":"5921-5933","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Novel organometallic chloroquine derivative inhibits tumor growth"],"prefix":"10.1002","volume":"119","author":[{"given":"Elizabeth A.","family":"Hall","sequence":"first","affiliation":[{"name":"The University of Vermont Cancer Center Burlington Vermont"},{"name":"Department of Medicine The University of Vermont Burlington 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