Hydroxychloroquine and Chloroquine as anti-cancer agents

'''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.

Introduction

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 also for treating discoid and systemic lupus erythematosus and rheumatoid arthritis. Although HCQ and CQ differ only by one hydroxyl group, the addition of this hydroxyl group results in an important decrease in toxicity, while the efficacy remains constant, at least for malaria [1]. Both drugs are available as generic products and mentioned on the WHO list of essential medicines. Frequently used trade names of CQ include Avloclor, Nivaquine or Aralen, and the most frequently used trade name for HCQ is Plaquenil.

The mechanisms of action of CQ and HCQ against the malarial Plasmodium parasite and against the auto-immune disorders for which they are approved are well known [2–6].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718030/

http://archive.is/kQq0o

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718030/pdf/can-11-781.pdf

Chloroquine-containing Compounds THERAPEUTIC APPLICATIONS

Treating neuropathy

Anti-cancer agents

Treating degenerative diseases

Anti-plasmodial agents

Against autoimmune diseases

Resolving inflammation and pain

Treating cardiovascular diseases

Anti-viral agents

Treating metabolic disorder

Modification of melanin synthesis

from Figure 3.

Various therapeutic applications of chloroquine and chloroquine-containing compounds

(page 1005)

Chloroquine-containing compounds: a patent review (2010 – 2014)

Introduction

Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented.

https://www.tandfonline.com/doi/full/10.1517/13543776.2015.1050791

http://archive.is/wip/TMtAl

>>8897904

forgot the PDF url

https://www.tandfonline.com/doi/pdf/10.1517/13543776.2015.1050791?needAccess=true

>>8897904

Expanding horizons for clinical applications of chloroquine, hydroxychloroquine, and related structural analogues

2019

Several experimental and clinical studies have transformed the traditional antimalarial role of chloroquine (CHQ) and related structural analogues to potent therapeutic agents for a host of nonmalarial indications. The expanding clinical applicability for these drugs includes rheumatological and cardiovascular disorders (CVD), chronic kidney disease (CKD), oncology, and a variety of nonmalarial infections. These clinical advancements are primarily related to pleiotropic pharmacological actions of these drugs, including immunomodulation, anti-inflammatory properties, and capabilities of inducing autophagy and apoptosis at a cellular level. Historically, many clinical benefits in nonmalarial indications were first recognized through serendipitous observations; however, with numerous ongoing systematic clinical studies, the clinical horizons of these drugs have a promising future.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905642/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905642/pdf/dic-2019-9-1.pdf