Elsevier

European Journal of Pharmacology

Volume 771, 15 January 2016, Pages 139-144
European Journal of Pharmacology

Review
Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies

https://doi.org/10.1016/j.ejphar.2015.12.017Get rights and content

Abstract

Chloroquine, a drug used for over 80 years to treat and prevent malaria and, more recently, to treat autoimmune diseases, is very safe but has a plethora of dose-dependent effects. By increasing pH in acidic compartments it inhibits for example lysosomal enzymes. In the context of cancer, Chloroquine was found to have direct effects on different types of malignancies that could potentiate chemotherapies. For example, the anti-malaria drug may inhibit both the multidrug-resistance pump and autophagy (mechanisms that tumor cells may use to resist chemotherapies), intercalate in DNA and enhance the penetration of chemotherapeutic drugs in cells or solid cancer tissues. However, these activities were mostly demonstrated at high doses of Chloroquine (higher than 10 mg/kg or 10 mg/l i.e. ca. 31 μM). Nevertheless, it was reported that daily uptake of clinically acceptable doses (less than 10 mg/kg) of Chloroquine in addition to chemo-radio-therapy increases the survival of glioblastoma patients (Sotelo et al., 2006, Briceno et al., 2007). However, the optimal dose and schedule of this multi-active drug with respect to chemotherapy has never been experimentally determined. The present article reviews the several known direct and indirect effects of different doses of Chloroquine on cancer and how those effects may indicate that a fine tuning of the dose/schedule of Chloroquine administration versus chemotherapy may be critical to obtain an adjuvant effect of Chloroquine in anti-cancer treatments. We anticipate that the appropriate (time and dose) addition of Chloroquine to the standard of care may greatly and safely potentiate current anti-cancer treatments.

Introduction

Chloroquine (N′-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine), a chemically synthesized compound that is structurally related to the natural product Quinine from Cinchona bark, can cure malaria. Although Quinine has been used since the 17th century to treat fever and malaria, Chloroquine, which has a higher activity and is entirely synthetic, arrived on the market during World War II. Chloroquine remains a widely used drug for the prophylaxis and treatment of malaria. Interestingly, the mechanisms of action of this “old” drug on Plasmodium are still being revealed (Schlitzer, 2007). However, it is agreed that the main toxic activity of Chloroquine for the parasite is due to the binding of the drug to ferriprotoporphyrin IX, which comes from the digestion of hemoglobin imported in the pathogen's digestive vacuole where Chloroquine accumulates (Chloroquine becomes protonated at acidic pH levels and thus accumulates in all acidic cellular compartments). Ferriprotoporphyrin IX is toxic to the parasite and is usually disposed by the formation of an insoluble polymer called hemozoin. By preventing this disposal, Chloroquine induces death in Plasmodium.

The usual dose of Chloroquine to control malaria ranges from 100 mg in one uptake a week (prophylaxis) to 300 mg daily (therapy), which could be considered as a maximal dose of approximately 5 mg/kg/day. Although safe below 10 mg/kg/day, a cumulative total dose of 50–100 g in long term usage (i.e., over 160 days of daily uptake of 300 mg) has been associated to retinopathy. Above 20 mg/kg, Chloroquine can cause serious toxic effects. The lowest oral lethal dose of Chloroquine is 86 mg/kg (Taylor and White, 2004). In the remainder of the review, I suggest that 10 mg/kg (10 mg/l i.e. ca. 31 μM) is the maximum realistic clinical dosage of Chloroquine. Thus, effects of Chloroquine (Table 1) recorded in vitro only at concentrations higher than 10 mg/l (higher than 31 μM) or in animals only at dosages higher than 10 mg/kg/day may generally not be relevant for translational studies. In the following, for clarity reasons and to allow direct comparisons between in vitro and in vivo results, all Chloroquine concentrations will be given in mg/l and mg/kg respectively, knowing that 1 mg/l of Chloroquine is approximately 31 μM.

Section snippets

Chloroquine dose and cancer

In vitro tumoricidal activities of Chloroquine were reported in the seventies in the range of approximately 30 mg/l for lymphoma cells and approximately 20 mg/l for melanoma cells (Bedoya, 1970). Marked inhibition of cancer cell growth (reaching IC50 values) in 24 h in vitro assays by Chloroquine is found at doses above 10 mg/l (A549 human lung cancer cells (Fan et al., 2006), CT26 mouse colon carcinoma cells (Zheng et al., 2009), 4T1 mouse mammary carcinoma cell line (Jiang et al., 2010), MCF-7

Focus on Chloroquine's activities that are achievable at a daily dose below 10 mg/kg

As detailed above, Choroquine may be toxic to cancer stem cells at acceptable doses in vivo. Therefore, Chloroquine could act as an adjuvant in anti-cancer treatments that are efficacious against differentiated cancer cells but fail to eradicate cancer stem cells. In addition, induction of vacuolization, inhibition of MRP and buffering of the tumor milieu are activities that validate Chloroquine as a chemosensitizer. The anti-malaria drug may potentiate the efficacy of anti-cancer

Discussion

In heterogeneous malignant tissues where malignant cells, somatic cells, immune cells and the vasculature interact to potentiate or limit tumor growth, Chloroquine can have a plethora of potentially opposite effects. It may theoretically potentiate the toxicity of anti-cancer treatments by triggering several death mechanisms, inhibiting multidrug resistance pumps, inhibiting autophagy, improving drug-penetration, favoring the presentation of MHC epitopes, or intercalating into DNA or, in

Conflict of interest

The author declares that he has no conflict of interest.

Acknowledgments

This work was supported by the Julius Müller Stiftung and the Kurt und Sente Herrmann Stiftung.

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