Editors' ChoiceCancer

Where and How Chloroquine Fights Cancer

Sci. Signal.  19 Aug 2014:
Vol. 7, Issue 339, pp. ec217
DOI: 10.1126/scisignal.2005810

Chloroquine is an antimalaria drug that also suppresses tumor growth and metastasis. Chloroquine neutralizes the pH of intracellular compartments, thereby disrupting the endosomal trafficking and lysosomal function. Whereas chloroquine impairs autophagy and proliferation in tumor cells, Maes et al. found that chloroquine suppressed the growth and metastasis of melanoma by acting on tumor-associated blood vessels independently of its effects on autophagy. Mice injected daily with chloroquine showed slower growth and less lung metastasis of subcutaneous melanoma xenografts. However, chloroquine did not suppress the invasion of cultured cancer cells into Matrigel, and lung colonization was not reduced by exposure of cancer cells to chloroquine prior to intravenous injection in mice. Additionally, whereas pretreating mice with chloroquine improved the delivery to and increased the toxicity of cisplatin in xenografts, no enhanced effect was observed in cultured cells, suggesting that chloroquine affected the cancer cell microenvironment rather than the cancer cells themselves. Structurally disorganized and functionally abnormal vasculature in the tumor milieu is a feature of many solid cancers and can limit delivery of anticancer drugs. Staining for endothelial and melanoma cell markers in sections from surgically removed xenografts showed that chloroquine (i) reduced vessel density, disorganization, and leakage; (ii) increased vessel coverage by pericytes (a marker of vessel maturation); and (iii) decreased tumor cell intravasation. These effects were not mimicked by inhibiting autophagy in endothelial cells.

Notch1, a protein that promotes endothelial cell quiescence, is activated through endosomal internalization and proteolysis. In cultured endothelial cells, chloroquine increased the accumulation of Notch1 in late endosomes and the abundance and half-lives of the Notch1 proteolytic fragments NEXT and NICD, the latter of which regulates transcription. Increased mRNA amounts of the endogenous Notch1 targets HEY1 and HES1 and experiments with a luciferase reporter gene indicated increased Notch1 signaling in endothelial cells exposed to chloroquine. Silencing Notch1 or pharmacologically inhibiting NICD production in endothelial cells in culture, or deleting endothelial cell–specific Notch1 in mice, abrogated the effects of chloroquine on endothelial cells in culture and chloroquine-induced vessel normalization and inhibition of xenograft growth and metastasis in mice. The findings suggest that chloroquine suppresses metastasis by enhancing Notch signaling to normalize the tumor-associated vasculature. These vessels may enable immune cells to more effectively reach the tumors and may improve delivery of chemotherapeutic drugs.

H. Maes, A. Kuchnio, A. Peric, S. Moens, K. Nys, K. De Bock, A. Quaegebeur, S. Schoors, M. Georgiadou, J. Wouters, S. Vinckier, H. Vankelecom, M. Garmyn, A.-C. Vion, F. Radtke, C. Boulanger, H. Gerhardt, E. Dejana, M. Dewerchin, B. Ghesquière, W. Annaert, P. Agostinis, P. Carmeliet, Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 26, 190–206 (2014). [PubMed]