Novel organometallic chloroquine derivative inhibits tumor growth. Issue 7 (25th March 2018)

• Record Type: Journal Article
• Authors: Hall, Elizabeth A.; Ramsey, Jon E.; Peng, Zhihua; Hayrapetyan, Davit; Shkepu, Viacheslav; O'Rourke, Bruce; Geiger, William; Lam, Kevin; Verschraegen, Claire F.
• Is Part Of: Journal of cellular biochemistry. Volume 119:Issue 7(2018)
• Page Start: 5921
• Page End: 5933
• Publication Date: 2018-03-25
• Subjects: autophagy -- chloroquine -- lysosome -- melanoma -- vemurafenib‐resistance; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.26787
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: 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. Abstract : The cellular process of autophagy has emerged as a viable target in the treatment of many tumor types. Efforts are underway to optimize the anti‐malarial compound, chloroquine, to improve its ability to block autophagy in the fight against cancer. Here, we report a novel organometallic derivative of chloroquine, termed Cymanquine, that displays improved anti‐autophagy properties, and the capacity to slow tumor growth in vivo.