Repurposing Drugs in Oncology (ReDO)—chloroquine and hydroxychloroquine as anti-cancer agents

Abstract

Chloroquine (CQ) and hydroxychloroquine (HCQ) are well-known 4-aminoquinoline antimalarial agents. Scientific evidence also supports the use of CQ and HCQ in the treatment of cancer. Overall, preclinical studies support CQ and HCQ use in anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they are able to sensitise tumour cells to a variety of drugs, potentiating the therapeutic activity. Thus far, clinical results are mostly in favour of the repurposing of CQ. However, over 30 clinical studies are still evaluating the activity of both CQ and HCQ in different cancer types and in combination with various standard treatments. Interestingly, CQ and HCQ exert effects both on cancer cells and on the tumour microenvironment. In addition to inhibition of the autophagic flux, which is the most studied anti-cancer effect of CQ and HCQ, these drugs affect the Toll-like receptor 9, p53 and CXCR4-CXCL12 pathway in cancer cells. In the tumour stroma, CQ was shown to affect the tumour vasculature, cancer-associated fibroblasts and the immune system. The evidence reviewed in this paper indicates that both CQ and HCQ deserve further clinical investigations in several cancer types. Special attention about the drug (CQ versus HCQ), the dose and the schedule of administration should be taken in the design of new trials.

Lysosomal membrane permeabilization and cell death

“…Examples of CADs include the antimalarial agent chloroquine (CQ) and its derivatives, which have been used to treat several human diseases, albeit with severe side effects. Combinations of CQ and other drugs have been developed to treat cancer and autoimmune diseases . CADs have been extensively researched and are being studied as potential anticancer agents, and it has been speculated that CAD treatment may enhance the cellular accumulation of secondarily administered amine drugs .…”

Re-purposing Chloroquine for Glioblastoma: Potential Merits and Confounding Variables

“…At the physiological pH of 7.4, CHQ is unprotonated and highly membrane-penetrating (12). Once inside the cell, CHQ accumulates in acidic compartments and becomes protonated.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…14 This event was shown in Figure 1. 12,19 The easy synthesis of quinolines with selected chemical properties and their environmental sustainability [20][21][22] are added bonuses for their use in research and clinics, if proven to be effective anticancer drugs. Autophagy enables cellular adaptation to increased mutagenic load or to changes in nutrient concentrations.…”

“…10 The outcome of autophagy, therefore, becomes an important variable and a criterion in the evaluation of the effects of CQ on cancer cells. Several clinical trials that have included CQ or its analogs in combination with other anticancer agents have been initiated and the results of a number of them have been evaluated, with inhibition of autophagy as one of the outcome measures 11,12 (updated information is available at https://clinicaltrials.gov/ct2/results?cond=cancer&term= chloroquine&cntry=&state=&city=&dist=). It is important to note that the inhibition of autophagy is a crucial factor for the success of radiation therapy as well.…”