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.
Highlights
Chloroquine (CQ) and hydroxychloroquine (HCQ) are both 4-aminoquinoline agents that have been used for more than 70 and 50 years, respectively, to prevent or to treat malarial infections and later for treating discoid and systemic lupus erythematosus and rheumatoid arthritis
In a pilot retrospective study, 25 stage-IV cancer patients who had no clinical response to maximally tolerated chemotherapy and to first-line metronomic chemotherapy were treated with sirolimus (2 mg/day) and the autophagy inhibitor HCQ (400 mg/ day) in addition to their current metronomic chemotherapy for at least three months
Most clinical evidence was found in patients with glioblastoma and brain metastases and in patients with BRAF mutations, but some promising ecancer 2017, 11:781 effects have been reported in patients with lung cancer, multiple myeloma and sarcoma as well
Summary
Chloroquine (CQ) and hydroxychloroquine (HCQ) are both 4-aminoquinoline agents that have been used for more than 70 and 50 years, respectively, to prevent or to treat malarial infections and later for treating discoid and systemic lupus erythematosus and rheumatoid arthritis. In a pilot retrospective study, 25 stage-IV cancer patients (various types) who had no clinical response to maximally tolerated chemotherapy and to first-line metronomic chemotherapy were treated with sirolimus (2 mg/day) and the autophagy inhibitor HCQ (400 mg/ day) in addition to their current metronomic chemotherapy for at least three months. Existing anti-cancer therapies often induce pro-survival autophagy in cancer cells, which is associated with therapeutic resistance Because of their ability to inhibit autophagy, CQ and HCQ are able to sensitise tumour cells to chemotherapy and radiation. These drugs are often tested in (pre)clinical research in combination with other anti-cancer therapies. CQ analogues and other more specific autophagy inhibitory agents are under investigation for the treatment of cancer patients (e.g. Lys05) [142,143,144,145,146]
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