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.

Keywords: Chloroquine; Hydroxychloroquine; autoimmune; autophagy; cancer; malaria.

Figure 1

(A) Structure of Chloroquine (B) Structure of Hydroxychloroquine.

Figure 2

Summary of proposed mechanisms of actions of CQ.

Figure 3

The impact of chloroquine and hydroxychloroquine on endosomal and lysosomal function. (A) Endosomal internalization of ligands allows for cell signaling. This process requires an acidic environment which CQ inhibits, preventing downstream signaling through endocytic TLRs and the NOX complex. (B) CQ induces lysosomal membrane permeabilization, leading to cell death. (C) CQ prevents lysosomes from merging with autophagosomes in the process of autophagy through lysosomal alkalinization.

Figure 4

Inhibition of thrombus formation and NETosis. Thrombus formation driven by platelet-derived extracellular vesicles (PEVs) and antibody-induced platelet activation is inhibited by CQ. CQ also has a complex interference with NETosis, shown in the figure via inhibition of RAGE-mediated autophagy, HMGB1 release, and activation of PAD4, NOX, and TLRs.

Figure 5

(A) CQ upregulates C-X-C Chemokine Receptor Type 4 (CXCR4) degradation. (B) CQ impedes CXCR4 signaling following HMGB1 activation. (C) CQ prevents HMGB1 release. (D) CQ hinders RAGE-mediated CXCR4 upregulation.

Figure 6

The influence of CQ on intracellular calcium concentration. CQ inhibits increases in intracellular calcium via calcium ionophores, thrombin (TB), and phorbol-myristate-acetate (PMA). Elevated intracellular calcium can stimulate release of phospholipase A2 (PLA2), leading to arachidonic acid (AA) liberation and subsequent platelet activation.