Chloroquine and hydroxychloroquine in antineoplastic therapy based on autophagy-related mechanisms

Drug repurposing, also known as "redirection" or "repurposing," is a new use of known and established compounds for new therapeutic indications
.
Drug redirection provides the opportunity to identify drugs to treat rare diseases, including certain types of cancer
.
In addition, in addition to reducing the risks and availability associated with new drug development, it saves time and money and increases productivity
.
In addition, the distance between drug discovery and commercial availability is shortened because previous records allow access to pharmacodynamics, pharmacokinetics, toxicity, drug interactions, and clinical databases
.

In addition to malaria, chloroquine (CQ) and hydroxychloroquine (HCQ) are currently used to relieve rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome and sarcoidosis
.
They are included in the World Health Organization's list of essential medicines as safe and effective medicines
needed by health systems.
In 2014, HCQ was approved in India as a third- or fourth-line treatment for type 2 diabetes, considering its beneficial side effects associated with systemic diseases associated with metabolic syndrome and better control of atherosclerosis, hyperglycemia, and hyperlipidemia
.
In particular, CQ and HCQ have also been widely reported as potential anticancer agents
.

Although the exact mechanism of the anticancer effects of CQ and HCQ is not fully understood, some mechanisms
have been proposed.
Among them, the inhibition of autophagy is discussed the most and accepted
.
Autophagy is a well-known evolutionary mechanism by which cells self-degrade in mammalian systems in response to different stimuli/stresses, including food deprivation, high temperatures, hypoxia, and xenobiotic
.

Chloroquine and hydroxychloroquine are the most commonly used medications for the relief of acute and chronic inflammatory diseases.
In this review, the authors reviewed the use
of CQ and HCQ in antitumor therapy based on the mechanism of autophagy.
These molecules disrupt/interrupt autophagosome-lysosomal fusion at the initial stage and enhance the antiproliferative effect
of chemotherapy drugs.
When used as an adjunctive option in anti-cancer clinical trials, their sensitizing effect
on chemotherapy.
However, human-related MDR genes are also at risk of developing chemical or radiological resistance because cancer cells are well able to throw 4-aminoquinoline
from digestive juices.

In conclusion, chloroquine and hydroxychloroquine cause the accumulation of acidic vesicle organelles and interrupt autophagosome-lysosomal fusion
.
This explains, at least in part, the sensitization of
chemotherapy when they are used as an adjunctive option in anti-cancer clinical trials.
In addition, they have antitumor mechanisms unrelated to autophagy, including apoptosis and necroposis and immunomodulating/anti-inflammatory properties
.

References: Ferreira PMP, Sousa RWR, Ferreira JRO, Militão GCG, Bezerra DP.
Chloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms.
Pharmacol Res.
2021 Jun; 168:105582.
doi: 10.
1016/j.
phrs.
2021.
105582.
Epub 2021 Mar 26.
PMID: 33775862.