Biologic Functions of Hydroxychloroquine in Disease: From COVID-19 to Cancer

Abstract

Chloroquine (CQ) and Hydroxychloroquine (HCQ), initially utilized in the treatment of malaria, have now developed a long list of applications. Despite their clinical relevance, their mechanisms of action are not clearly defined. Major pathways by which these agents are proposed to function include alkalinization of lysosomes and endosomes, downregulation of C-X-C chemokine receptor type 4 (CXCR4) expression, high-mobility group box 1 protein (HMGB1) inhibition, alteration of intracellular calcium, and prevention of thrombus formation. However, there is conflicting data present in the literature. This is likely the result of the complex overlapping pathways between these mechanisms of action that have not previously been highlighted. In fact, prior research has focused on very specific portions of particular pathways without describing these in the context of the extensive CQ/HCQ literature. This review summarizes the detailed data regarding CQ/HCQ’s mechanisms of action while also providing insight into the overarching themes. Furthermore, this review provides clinical context to the application of these diverse drugs including their role in malaria, autoimmune disorders, cardiovascular disease, thrombus formation, malignancies, and viral infections.

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

“…On the other hand, recent studies indicate that a series of mutations such as RAS, BRAF, and p53 can alter the vulnerability of cancer cells to death and their sensitivity to cytotoxic drugs. Thus, chemotherapy-induced Most importantly, CQ and HCQ have been intensively investigated as potential tools for the treatment of cancers of various origins [3,4,15,16]. Antitumor CQ/HCQ activity as a single agent or as adjuvant therapy in combination with widely used cytotoxic compounds has been probed in a long list of malignancies.…”

“…In acidic environments, they undergo protonation and remain trapped inside, thus causing alkalinization. This process inhibits the ability of enzymes to degrade unwanted material and blocks the survival mechanisms in cancer cells which allows them to proliferate [3,4].…”

“…However, CQ/HCQ are not specific autophagy inhibitors, as they can affect other cellular processes beyond autophagy (Figure 2). Among their reported therapeutic effects on cancer cells are autophagy-independent disturbances in chemokine signaling, increased ROS production, mitochondria damage, the induction of apoptosis, modifications in the tumor microenvironment, the normalization of tumor-associated vascularization, the prevention of pro-thrombotic processes, the activation of antitumor immune responses, the inhibition of tumor-promoting intermediates via tumor-associated macrophages, the negative modulation of cancer-associated fibroblasts, the modulation of metabolic responses, the alteration of intracellular calcium balance, and the disruption of membrane stability [2][3][4].…”

“…However, during the last few decades, CQ and HCQ have been probed for a variety of other diseases. These drugs have a wide therapeutic index and well-established dose safety profiles, and they are inexpensive and orally bioavailable, thus attracting the substantial interest of researchers and clinicians [4]. CQ was shown to be effective for anti-intestinal amebiasis caused by trophozoites of Entamoeba histolytica, which causes amebic dysentery [5].…”

“…Zika virus [9,10], human immunodeficiency virus (HIV) [11,12], and COVID-19, although the obtained results were inconsistent or negligible and revealed many side effects [13,14]. Most importantly, CQ and HCQ have been intensively investigated as potential tools for the treatment of cancers of various origins [3,4,15,16]. Antitumor CQ/HCQ activity as a single agent or as adjuvant therapy in combination with widely used cytotoxic compounds has been probed in a long list of malignancies.…”