Novel organometallic chloroquine derivative inhibits tumor growth

Elizabeth A. Hall, Jon E. Ramsey, Zhihua Peng, Davit Hayrapetyan, Viacheslav Shkepu, Bruce O'Rourke, William Geiger, Kevin Lam Georges, Claire F. Verschraegen

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5921-5933
Number of pages13
JournalJournal of Cellular Biochemistry
Volume119
Issue number7
DOIs
Publication statusPublished - Jul 2018

Keywords

  • autophagy
  • chloroquine
  • lysosome
  • melanoma
  • vemurafenib-resistance

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Hall, E. A., Ramsey, J. E., Peng, Z., Hayrapetyan, D., Shkepu, V., O'Rourke, B., Geiger, W., Lam Georges, K., & Verschraegen, C. F. (2018). Novel organometallic chloroquine derivative inhibits tumor growth. Journal of Cellular Biochemistry, 119(7), 5921-5933. https://doi.org/10.1002/jcb.26787