Abstract
The indiscriminate consumption of antimalarials against coronavirus disease-2019 emphasizes the longstanding clinical weapons of medicines. In this work, we conducted a review on the antitumor mechanisms of aminoquinolines, focusing on the responses and differences of tumor histological tissues and toxicity related to pharmacokinetics. This well-defined analysis shows similar mechanistic forms triggered by aminoquinolines in different histological tumor tissues and under coexposure conditions, although different pharmacological potencies also occur. These molecules are lysosomotropic amines that increase the antiproliferative action of chemotherapeutic agents, mainly by cell cycle arrest, histone acetylation, physiological changes in tyrosine kinase metabolism, inhibition of PI3K/Akt/mTOR pathways, cyclin D1, E2F1, angiogenesis, ribosome biogenesis, triggering of ATM-ATR/p53/p21 signaling, apoptosis, and presentation of tumor peptides. Their chemo/radiotherapy sensitization effects may be an adjuvant option against solid tumors, since 4-aminoquinolines induce lysosomal-mediated programmed cytotoxicity of cancer cells and accumulation of key markers, predominantly, LAMP1, p62/SQSTM1, LC3 members, GAPDH, beclin-1/Atg6, α-synuclein, and granules of lipofuscin. Adverse effects are dose-dependent, though most common with chloroquine, hydroxychloroquine, amodiaquine, and other aminoquinolines are gastrointestinal changes, blurred vision ventricular arrhythmias, cardiac arrest, QTc prolongation, severe hypoglycemia with loss of consciousness, and retinopathy, and they are more common with chloroquine than with hydroxychloroquine and amodiaquine due to pharmacokinetic features. Additionally, psychological/neurological effects were also detected during acute or chronic use, but aminoquinolines do not cross the placenta easily and low quantity is found in breast milk despite their long mean residence times, which depends on the coexistence of hepatic diseases (cancer-related or not), first pass metabolism, and comedications. The low cost and availability on the world market have converted aminoquinolines into “star drugs” for pharmaceutical repurposing, but a continuous pharmacovigilance is necessary because these antimalarials have multiple modes of action/unwanted targets, relatively narrow therapeutic windows, recurrent adverse effects, and related poisoning self-treatment. Therefore, their use must obey strict rules, ethical and medical prescriptions, and clinical and laboratory monitoring.
Highlights
About 1 in 6 deaths is due to cancer and about 70% of cancer deaths occur in low- and middle-income countries
To carry out a comprehensive and consistent analysis, we use only primary and secondary materials, including research articles, reviews, books, and government publications written in English, Portuguese, or Spanish. e bibliographic research was performed in the scientific databases ScienceDirect, Scopus, PubMed, and Scielo. e descriptors “autophagy,” “cell cycle,” “apoptosis,” “drug repurposing”, and “anti-tumor” were combined with “aminoquinoline” for a narrative scientific exploration
Since the morphological and flow cytometric investigations of chloroquine-treated CT-26 cells showed dissolved nuclei, condensation, swelling of organelles, and rupture of the cell membrane, these findings suggested that, instead of apoptosis, Receptor-interacting protein kinase 3 (RIP3)-dependent necroptosis was probably a reason for RIP3+-chloroquine-induced cell death [61, 70, 71]
Summary
About 1 in 6 deaths is due to cancer and about 70% of cancer deaths occur in low- and middle-income countries. E indiscriminate use of chloroquine and hydroxychloroquine as a first-line, adjuvant, or palliative drug(s) to treat victims of COVID-19 or to control new local outbreaks as a prophylactic [11, 12] emphasized the various longstanding clinical branches of drugs, including those against chronic disorders. Advantages such as low cost, long usage history, and market availability even in developing countries where malaria is endemic are reasons that explain, at least in part, the commercial triumph of these drugs, converting 4-aminoquinolines into “star drugs” for their reuse in the pharmaceutical industry. To carry out a comprehensive and consistent analysis, we use only primary and secondary materials, including research articles, reviews, books, and government publications written in English, Portuguese, or Spanish. e bibliographic research was performed in the scientific databases ScienceDirect, Scopus, PubMed, and Scielo. e descriptors “autophagy,” “cell cycle,” “apoptosis,” “drug repurposing”, and “anti-tumor” were combined with “aminoquinoline” for a narrative scientific exploration
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