Evidence that chloroquine’s anti-tumour activity is not related to inhibiting autophagy

Chloroquine is an anti-malarial agent which has recently been applied to cancer and is in several clinical trials [1]. It’s anti-cancer mechanism of action was thought to relate to its ability to inhibit autophagy in cancer cells, however recent studies suggest that its anti-tumour effects are unrelated to cancer cell autophagy inhibition.

It has been found that chloroquine inhibits cancer cell line proliferation equally well in macroautophagy knockout vs parental cell line combinations suggesting a mechanism of action other than autophagy inhibition. Interestingly autophagy knockout did not significantly decrease cancer cell line proliferation compared with the parental line. Furthermore chloroquine application but not autophagy knockout synergised with tyrosine kinase inhibitors to suppress cancer cell line proliferation [2]. Thus in vitro chloroquine’s synergistic and also its independent mechanism of action is not dependent on autophagy inhibition.

In vivo mouse models have found that chloroquine’s anti-proliferative effect on cancer cells is less important than its ability to normalise surrounding vasculature and improve the delivery of chemotherapeutics, highlighting its potential in combination therapy. Inhibition of endothelial cell autophagy did not recapitulate the effect of chloroquine on vascular normalisation suggesting additional mechanisms are responsible [3].

Thus chloroquine’s anti-tumour mechanism of action seems independent of autophagy inhibition at least in certain contexts. The exact cellular mechanisms that chloroquine modulates to alter tumour growth remain to be discovered.

Refs

  1. ‘Definition of Chloroquine – NCI Drug Dictionary – National Cancer Institute’. Accessed 4 February 2016. http://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=654729.
  2. Eng, Christina H., Zuncai Wang, Diane Tkach, Lourdes Toral-Barza, Savuth Ugwonali, Shanming Liu, Stephanie L. Fitzgerald, et al. ‘Macroautophagy Is Dispensable for Growth of KRAS Mutant Tumors and Chloroquine Efficacy’. Proceedings of the National Academy of Sciences 113, no. 1 (5 January 2016): 182–87. doi:10.1073/pnas.1515617113.
  3. Maes, Hannelore, Anna Kuchnio, Aleksandar Peric, Stijn Moens, Kris Nys, Katrien De Bock, Annelies Quaegebeur, et al. ‘Tumor Vessel Normalization by Chloroquine Independent of Autophagy’. Cancer Cell 26, no. 2 (11 August 2014): 190–206. doi:10.1016/j.ccr.2014.06.025.
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