Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

Abstract

Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of tumors of different origin to increase the efficacy of cytotoxic agents. Such a strategy can be effective in overcoming the resistance of cancer cells to standard chemotherapy or anti-angiogenic therapy. This review presents the results of the combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells, animal xenografts models, and in a few clinical trials. The effects of such an approach on the viability of cancer cells or tumor growth, as well as autophagy-dependent and -independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ, are summarized. Although the majority of experimental in vitro and in vivo studies have shown that CQ/HCQ can effectively sensitize cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Nevertheless, the pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, and the development of more specific inhibitors is required.

Keywords: animal xenografts; autophagy; chemotherapy; chloroquine; clinical trials; cultured cancer cells; hydroxychloroquine.

Figure 1

Chemical structure of chloroquine and hydroxychloroquine.

Figure 2

A simplified scheme of reported CQ/HCQ effects in cancer cells. The impact on lysosomal and endosomal systems, the disturbances in intracellular signaling, and the induction of mitochondria-dependent apoptosis are presented. X—inhibition, ROS—reactive oxygen species, Δψ—mitochondrial membrane potential, p—phosphorylation.

Figure 3

Anticancer effects of CQ/HCQ in experimental studies and in clinical trials. ↓—inhibition, ↑—enhancement.