Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 3288 2022-12-08 15:07:28 |
2 format Meta information modification 3288 2022-12-09 02:18:05 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Niemann, B.;  Puleo, A.;  Stout, C.;  Markel, J.;  Boone, B.A. Biologic Functions of Hydroxychloroquine in Disease. Encyclopedia. Available online: (accessed on 16 June 2024).
Niemann B,  Puleo A,  Stout C,  Markel J,  Boone BA. Biologic Functions of Hydroxychloroquine in Disease. Encyclopedia. Available at: Accessed June 16, 2024.
Niemann, Britney, Amanda Puleo, Conley Stout, Justin Markel, Brian A. Boone. "Biologic Functions of Hydroxychloroquine in Disease" Encyclopedia, (accessed June 16, 2024).
Niemann, B.,  Puleo, A.,  Stout, C.,  Markel, J., & Boone, B.A. (2022, December 08). Biologic Functions of Hydroxychloroquine in Disease. In Encyclopedia.
Niemann, Britney, et al. "Biologic Functions of Hydroxychloroquine in Disease." Encyclopedia. Web. 08 December, 2022.
Biologic Functions of Hydroxychloroquine in Disease

Chloroquine (CQ) and Hydroxychloroquine (HCQ), initially utilized in the treatment of malaria, have 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. 

Hydroxychloroquine Chloroquine malaria cancer

1. Introduction

Chloroquine (CQ) and its derivative, hydroxychloroquine (HCQ), are well-known, multi-use drugs with applications in anti-malarial and anti-viral treatment, autoimmune diseases, and neoplastic processes [1][2][3][4]. While CQ and HCQ have been used for decades, new uses continue to be discovered. However, despite their widespread use, the mechanism of action is poorly understood. In fact, numerous mechanisms with overlapping pathways have been proposed.

2. Biochemistry and Pharmacology

Chloroquine and hydroxychloroquine are 4-aminoquinolines with anti-malarial, anti-viral, anti-inflammatory, and anti-cancer applications [5]. Structurally, they differ by only one hydroxyl group. Though CQ has been in use for the better part of a century, its pharmacokinetics were not studied in detail until approximately the 1980s. Using liquid chromatographic techniques with diethyl ether extraction to identify CQ and desethylchloroquine (main metabolite), Gustafsson et al. studied chloroquine concentrations in healthy individuals after single dose administration with either intravenous (IV) or per os (PO) formulation. They found the drug could be detected in urine samples 23–52 days after administration with massive volumes of distribution (Vd) ranging from 111–285 L/kg [6]. Large Vd were further validated by Frisk-Holmberg et al. who showed up to 800 L/kg when calculated by plasma concentrations; however, whole blood concentrations were 8–10 times higher and, consequently, had Vd approximately 10 times lower [7]. This effect is explained by the finding that chloroquine is concentrated in erythrocytes and is approximately 2–5 times higher in red blood cells than in plasma [6]. Further explanation of such large Vd is likely due to the basic nature of chloroquine and its affinity for lysosomal uptake [8][9]. Bioavailability of solution and pill form has been reported ranging from 78% to nearly 100%, with the higher value coming from later studies. The high bioavailability is attributed to rapid distribution into erythrocytes and thus low plasma levels exposed to first pass hepatic metabolism [6][10]. Similar findings were observed in studies of chloroquine malaria treatment in children [11]. Pregnancy has been shown to decrease half-lives and Vd [12]. The limited amount of chloroquine and desethylchloroquine in plasma is bound to albumin [13][14]. Furthermore, plasma levels varied by enantiomer with (S)-chloroquine plasma levels being approximately 66% bound and (R)-chloroquine 42% bound [15]. Unmetabolized CQ is excreted primarily in urine [16]. A detailed reviewed of chloroquine pharmacokinetics was previously completed by White and more recently by Ducharme and Farinotti [16][17].

3. Alkalinization of Lysosomes and Endosomes

CQ and HCQ’s basic properties allow for the drugs to accumulate in, and alkalinize, the acidic environments of lysosomes and endosomes. Each of these organelles contribute to the processes of cell death and cell signaling. Endosomes play an important role in the entry and replication of several viruses, thrombus formation in autoimmune disorders, and cell signaling through endocytic Toll-like receptors (TLRs). Lysosomes, on the other hand, drive autophagy and cell death.
Autophagy is an important cellular process where catabolism of cellular components occurs in the settings of nutrient deprivation, hypoxia, and other cell stressors including chemotherapy and radiation [18]. This process can serve multiple purposes, such as energy production in hypoxic and nutrient-deprived environments, and clearance of damaged organelles and reactive oxygen species (ROS) [19].
Based on the initial stressor signal, different pathways are involved in activating autophagy. The common pathway converges on the formation of the autophagosome, a double membrane structure that encloses cellular components. The autophagosome then fuses with a lysosome, allowing for degradation of its contents via lysosome hydrolases [19][20]. CQ/HCQs alkalinization of lysosomes prevents this fusion, as well as impairs the function of lysosomal hydrolases, resulting in autophagy inhibition and impaired lysosome hydrolase function [21]. CQ’s known risk of ocular toxicity has been attributed to this dysfunction of lysosome hydrolases in retinal pigment epithelium (RPE). Lysosomal dysfunction has been shown to lead to an accumulation of lipofuscin, which can lead to retinal toxicity [22][23].
The consequences of autophagy inhibition are numerous. Autophagy has been implicated in carcinogenesis, disease progression, and even metastasis [21][24][25][26]. Tumors with high proliferation rates often outgrow their blood supply and thus, their source of nutrients. Autophagy can serve as a source of fuel in these settings, and therefore, it is no surprise increased rates of autophagy are found in many cancers [21][24][25][26][27]. Pancreatic cancer, for example, has a strong link to increased autophagy and tumor grade, resulting in poor prognosis [24][28]. Yang et al. demonstrated inhibition of autophagy, through genetic means or use of CQ, led to accumulation of ROS which induced DNA damage and decreased cancer cell growth in vitro. Furthermore, inhibition of autophagy with CQ resulted in tumor regression and prolonged survival in mouse models [29]. Likewise, cancer stem cells, which play an important role in tumor initiation, metastasis, recurrence, and chemoresistance, utilize autophagy, with CQ treatment leading to regression and improved outcomes [30][31].
Autophagy may also mediate resistance to chemotherapy. Upregulation of autophagy is seen following multiple chemotherapy agents [32]. To clarify the role of autophagy in chemotherapy resistance, genetic silencing of autophagy-related genes (ATGs) has been tested in the setting of chemoresistant cancer cell lines. Genetic silencing was shown to sensitize previously chemoresistant cells to therapy [33]. Hashimoto et al. demonstrated an increase in autophagy following treatment of pancreatic cancer cells with either 5-fluorouracil (5-FU) or gemcitabine. However, treatment in combination with chloroquine reduced autophagy and potentiated the antiproliferative effects of 5-FU and gemcitabine [34]. Glioblastoma cells were also found to utilize higher rates of autophagy to overcome treatment with Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF). Chloroquine and hydroxychloroquine reverse this resistance in multiple studies [35][36]. These studies indicate that although CQ/HCQ alone have shown antitumor effects, they may be best utilized as a combination therapy.
In addition to the effect on oncologic cells from autophagy, it also appears to play an important role in activating cancer supporting cells. Pancreatic stellate cells (PSCs) protect the tumor from the immune system’s antitumor defense by creating a strong, fibrous stroma around the tumor which decreases T cell infiltration. Endo et al. linked autophagy with PSC activation and, as with pancreatic cancer cells, associated this increased rate of autophagy to a poor prognosis. By inhibiting autophagy with chloroquine, the authors were able to demonstrate conversion of PSCs to a quiescent state as well as a decrease in extracellular matrix accumulation and tumor volumes [37]. Similarly, cancer associated fibroblasts (CAFs) in breast cancer enhance the growth and metastatic potential of breast tumors. Caveolin-1 (Cav-1) is a structural protein and transformation suppressor expressed by healthy fibroblasts. Breast cancer cells are able to downregulate the expression of Cav-1, leading to early disease progression and poor prognosis. Interestingly, CQ was able to restore Cav-1 expression, indicating cancer cells may use autophagy to degrade antitumor structures [27].
Autophagy also plays a role in multiple autoimmune diseases via antigen processing and presentation, T cell activation, and cytokine processing [38][39][40]. Overactivation of T cells results in the body incorrectly targeting self-antigens leading to cell death, extensive inflammation, and organ damage [41]. Through autophagy inhibition, CQ and HCQ prevent autoantigen presentation in antigen presenting cells and B cells, resulting in decreased T cell activation [40]. Rheumatoid arthritis (RA) results in a dysregulation in autophagy and is characterized by synovial inflammation, increased bone catabolism, and damage to cartilage and bone. RA patients develop autoantibodies, often to citrullinated proteins. Fibroblast-like synoviocytes (FLS) are found infiltrating cartilage and bone surfaces and can deposit collagen and α-smooth muscle actin causing synovial fibrosis. High levels of autophagy in RA FLS allow for prolonged survival and correlate with increased levels of antibodies against citrullinated proteins [38].
While lysosomes can support cell survival through autophagy, they can also promote cell death. Cell death can occur through cell necrosis or apoptosis, both of which can be impacted by lysosomes. Lysosomal death is initiated by lysosomal membrane permeabilization (LMP) which allows the translocation of lysosomal enzymes into the cytoplasm instigating cell death [42]. CQ and HCQ are capable of causing permeabilization of not only lysosomal membranes, but also mitochondrial and plasma membranes. Boya et al. showed that HCQ accumulation in lysosomes resulted in increased lysosomal volume followed by lysosomal, mitochondrial, and plasma membrane permeabilization [43]. Extensive permeabilization, as well as lysosomal hydrolase activity within the cytoplasm, resulted in cell death. LMP induction may be an additional mechanism by which CQ overcomes resistance to chemotherapy. For example, patients with non-small-cell lung cancer (NSCLC) unable to receive immunotherapy often receive chemotherapy. However, resistance forms quickly. CQ was shown to induce LMP leading to apoptosis of NSCLC cells [44]. This effect has also been demonstrated with CQ treatment in conjunction with PI3K/mTOR inhibitors [45][46].
Chloroquine’s role in the treatment of malaria has also been attributed to the alkalinization of a type of secondary lysosome called a digestive vesicle (DV) [47]. Malaria, caused by different species of the parasite Plasmodium, is characterized by parasitic invasion of host red blood cells (RBCs). Plasmodium degrades hemoglobin within DVs and utilizes the amino acid products. Heme is also released during this process and is toxic to parasites. However, in the acidic environment of DVs it is quickly converted to the nontoxic hemozoin. This process is inhibited in the setting of CQ induced alkalinization of DVs resulting in heme toxicity to parasites. Plasmodium quickly adapts, though, resulting in widespread CQ resistance. This is secondary to a mutation in the plasmodium falciparum chloroquine resistance transporter gene (pfcrt) which allows for the efflux of CQ out of DV through a transporter protein [48]. Specifically, the transporter takes on a configuration that produces an overall negative charge, attracting and sequestering positively charged compounds such as CQ [49].
Alkalinization of acidic compartments by CQ also impacts endosome function. Endosomes are a critical part of endocytosis, a process which propagates cell signaling and allows them to internalize aspects of the surrounding environment. Viruses commonly utilize endocytosis to gain entry into a cell. CQ has been shown to decrease intracellular viral accumulation of multiple viruses, including Borna virus, HIV, Hepatitis A, Zika virus, Hepatitis C, Dengue virus, and Ebola [50][51][52][53][54][55]. Viral replication is also dependent on organelle pH for intracellular trafficking, unpacking, and post-translational modification [54]. Importantly, other antiviral mechanisms have been proposed separate from the effects of CQ on organelle pH. CQ has been shown to inhibit glycosylation, a necessary process for the glycosylation of viral envelopes and subsequent release [50]. Another possible mechanism is proposed by the inhibition of arachidonic acid metabolism and activation of NFκB, thus decreasing transcription of viral DNA [56].
Some Toll-like receptors (TLRs) depend on endosomal function for the transmission of their signal. TLRs are transmembrane proteins with important functions in innate immunity and inflammation. The proteins are located either on the plasma membrane or endosomal membrane. Endocytic TLRs 3, 7, 8, and 9 require internalization of ligands to stimulate activity, a process which is inhibited by compartment alkalinization by CQ [57][58][59][60][61][62]. In fact, Rutz et al. identified CQs ability to inhibit TLR9 signaling to be pH dependent, supporting this proposed mechanism [63]. Endocytic TLRs are involved in sepsis-induced mortality and acute kidney injury (AKI) in mouse models. Treatment with CQ decreased AKI, TLR protein in the spleen, and systemic inflammation as well as improved the survival rate [64]. Likewise, treatment with CQ prevented bacterial DNA-induced TLR signaling of the inflammatory response to sepsis [65]. TLR inhibition has many downstream effects, including reduced cytokine production, and impaired recognition of immune complexes by endosomal TLRs in autoimmune diseases [66]. Additionally, TLR9 may have a role in the pathogenesis of type I diabetes. CQ treatment decreased development of diabetes and improved islet cell function. Of note, there is evidence that CQs effect on TLRs may extend beyond pH modifications. Kuznik et al. recently demonstrated CQs effect on TLRs is present even with only minimal changes in endosomal pH. In fact, CQ could directly bind ligands in order to prevent their binding to TLRs. Further revealed was CQ’s capability to directly bind TLR ligands, preventing their binding to receptors. CQ was found to inhibit the function of TLRs 3, 7, and 9, but acted as an agonist for TLR8 [67]. Similarly, Zhang et al. demonstrated the reversibility of CQs effect via addition of a TLR9 agonist, again contradicting the theory of alkalinization as the sole source of the mechanism [68].

4. C-X-C Chemokine Receptor Type 4

C-X-C chemokine receptor type 4 (CXCR4) is a chemokine receptor that, along with its ligand C-X-C motif chemokine ligand 12 (CXCL12), impacts many physiologic as well as pathologic processes. The CXCR4/CXCL12 axis is widely expressed throughout the human body, and their downstream effects of receptor binding result in gene transcription, cell proliferation and survival, and cellular adhesion and migration [69][70]. The embryonic vitality of the CXCR4 receptor and chemokine has been demonstrated in murine models; and the physiologic functions of embryogenesis, hematopoiesis, brain development, and leucocyte trafficking towards sites of inflammation have been well established [70][71][72][73][74]. Pathologically, a role in multiple autoimmune diseases, stroke, and the cellular entry of human immunodeficiency virus has also been studied [70][74][75][76]. In oncologic disease, CXCR4 has been found to be frequently overexpressed in malignant cells and linked to primary tumor growth, angiogenesis, tumor invasion of surrounding tissues, and metastasis [69][70][73][74][77][78][79]. Due to the pathologic function of this axis, it has gained attention from researchers searching for a viable inhibitor. Chloroquine-containing products have been found to downregulate CXCR4 expression [69][80][81].
In 2012, Kim et al. observed decreased CXCR4-mediated pancreatic cancer cell signaling and proliferation in vitro [82]. Further in vitro experimentation by Balic et al. in 2014 showed a significant decrease in the number of circulating tumor cells in pancreatic cancer treated with chloroquine. The inhibition was found to reduce phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) and showed potential to assist with the control of metastatic disease [83]. Inhibition of CXCR4 with CQ has also been shown to delay tumor progression in esophageal cancer in mice [84]. Through this pathway of inhibition, effects on tumor vasculature and immune system function have also been noted [85]. In 2016, Yu et al. published two studies where synthesized CQ was used to decrease cell surface expression of CXCR4 in oncologic cells and proved to have both antimetastatic properties in addition to causing less toxicity than its parent drug, hydroxychloroquine [86][87]. While this mechanism of action for chloroquine products has not been the most studied, there is evidence supporting its further research and how it may help the treatment of oncologic disease.

5. High-Mobility Group Box 1 Protein

High-mobility group box 1 protein is a DNA-binding protein with both intra- and extracellular functions through many receptors such as that found in advanced glycation end products (RAGE), T cell immunoglobulin domain and mucin domain-3, and TLR4. HMGB1s downstream effects are abundant and include the following: transcription regulation, autophagy initiation, carcinogenesis, angiogenesis, potentiation of inflammation and ischemia, cytokine production, hypercoagulability, NETosis, and sepsis [58][88][89][90][91][92][93][94][95]. In the presence of ROS, there is an upregulation of RAGE expression, which binds HMGB1 resulting in the activation of multiple pathways. First, TLR9 can be stimulated, resulting in the release of inflammatory cytokines. Second, IL-6 release activates STAT3, a process that can both enhance autophagy and increase CXCR4 expression. Third, the RAGE-HMGB1 complex also directly triggers autophagy. As discussed, CQ can impact multiple aspects of these pathways, including TLR9, CXCR4, and autophagy. However, CQ has also been shown to inhibit release of HMGB1 in septic mice resulting in improved mortality [92]. Furthermore, it prevented release of HMGB1 from monocytes following stimulation with LPS or IFNγ [96]. This impact has not yet been studied extensively in other pathologies but represents an additional potential target of CQ.

6. Alteration of Intracellular Calcium

Intracellular calcium stores are an important part of cell signaling with increased intracellular calcium levels resulting in signal propagation. Platelet aggregation, for instance, often requires alterations in intracellular calcium levels. Platelet aggregation can be induced by multiple stimulants, including phorbol-myristate-acetate (PMA), calcium (Ca) ionophores, and thrombin.
PMA and thrombin act via protein kinase C (PKC), resulting in a mobilization of intracellular calcium stores. On the other hand, Ca ionophores do not require membrane receptors and utilize influx of extracellular calcium. Ca ionophore and thrombin stimulation both induce release of phospholipase A2 (PLA2), leading to arachidonic acid (AA) liberation from plasma membrane phospholipids. The arachidonic acid cascade is critical for platelet aggregation as it yields thromboxane A2 (TXA2) which is important for aggregation and vasoconstriction. CQ is capable of inhibiting platelet aggregation secondary to PMA, Ca ionophore, and thrombin stimulation; however, it is less potent in relation to Ca ionophore stimulation. This difference may indicate that CQ plays more prominence on intracellular calcium than extracellular [97][98]. Research has shown CQ can also inhibit the arachidonic acid pathway via inhibition of PLA2, leading to reduction in TXA2 production [98][99].
PAD4 function has also been shown to be dependent on high intracellular calcium levels. PAD4 is an enzyme that citrullinates DNA histones resulting in decondensed chromatin. Its actions are essential to NETosis as PAD4 deficient mouse neutrophils are unable to form NETs [100]. PAD4 inhibitors also reduce NET formation in mouse and human neutrophils [101]. As discussed, NETs play an important role in multiple stages of cancer, autoimmune disease, and thrombus formation. PAD4 function disruption via alteration of intracellular calcium stores may be yet another mechanism by which HCQ inhibits NET formation.

7. Prevention of Thrombosis

Autoimmune diseases such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) have increased rates of both arterial and venous thrombi [102]. In particular, APS is an autoimmune disorder characterized by recurrent thrombosis and pregnancy losses and can occur as a primary disorder or in conjunction with SLE. APS antibodies (aPL) include lupus anticoagulant, anticardiolipin antibodies, or anti-β2 glycoprotein I antibodies [103]. APS antibodies create a pro-thrombotic environment via multiple pathways, such as interference with annexin A5, an anticoagulant protein found in both adult vasculature and the placenta. The A5 protein forms a crystal that covers phospholipid membranes to prevent interaction with coagulation enzymes; however, aPLs bind annexin A5, thus inhibiting the formation of this protective shield. HCQ not only restores the original crystal layer, but also induces the formation of a second crystal layer over the anti-β2 glycoprotein I binding sites [104]. Furthermore, HCQ is capable of preventing aPL binding to the phospholipid bilayer, as well as reversing the effects of aPLs, including platelet activation, increased TF expression, increased GPIIb/IIIa expression, and increased thrombin and thrombin receptor peptide agonist generation [105][106][107][108][109][110].
aPLs may also induce thrombus formation via activation of NADPH oxidase (NOX). NOX mediates multiple inflammatory pathways, including TNFα and IL-1β signaling, and has been shown to influence endothelial dysfunction following stimulation by aPL [107][111]. The NOX ligand-receptor complex requires entrance into the endosome in order for downstream signaling to occur resulting in reactive oxygen species (ROS) production and thrombus formation. As discussed, CQ and HCQ affect endosomal function; therefore, it is no surprise that HCQ is capable of inhibiting ROS and thrombi production [112][113]. Furthermore, HCQ reverses endothelial dysfunction secondary to aPL-induced endothelial nitric oxide synthase (eNOS) inhibition and upregulation of adhesion molecules [112]. Endothelial dysfunction reversal led to decreased mesenteric thrombi in APS mice and may be mediated by HCQ activating extracellular signal-regulated kinase 5 (ERK5) [106][114]. ERK5 has been shown to have endothelial protective effects, including inhibition of leukocyte-endothelial interaction, adhesion molecule expression, and the promotion of laminar flow-induced eNOS expression [115].
Patients are often found to be hypercoagulable following a trauma. Many reasons for this have been identified including the release of platelet-derived extracellular vesicles (PEVs). Although the exact mechanism and function of PEVs is unknown, they are believed to serve initially in promoting hemorrhage control. However, persistent release of PEVs can lead to a pro-thrombotic state and increased thrombin levels. Dyer et al. demonstrated that HCQ is capable of inhibiting the release of PEVs following injury with subsequent decreased thrombus burden in a murine deep vein thrombosis (DVT) model [116].


  1. Goldman, L.; Cole, D.P.; Preston, R.H. Chloroquine diphosphate in treatment of discoid lupus erythematosus. J. Am. Med. Assoc. 1953, 152, 1428–1429.
  2. Pillsbury, D.M.; Jacobson, C. Treatment of chronic discoid lupus erythematosus with chloroquine (aralen). J. Am. Med. Assoc. 1954, 154, 1330–1333.
  3. Cooper, R.G.; Magwere, T. Chloroquine: Novel uses & manifestations. Indian J. Med. Res. 2008, 127, 305–316.
  4. Manic, G.; Obrist, F.; Kroemer, G.; Vitale, I.; Galluzzi, L. Chloroquine and hydroxychloroquine for cancer therapy. Mol. Cell. Oncol. 2014, 1, e29911.
  5. Njaria, P.M.; Okombo, J.; Njuguna, N.M.; Chibale, K. Chloroquine-containing compounds: A patent review (2010–2014). Expert Opin. Ther. Patents 2015, 25, 1003–1024.
  6. Gustafsson, L.L.; Walker, O.; Alvan, G.; Beermann, B.; Estevez, F.; Gleisner, L.; Lindstrom, B.; Sjoqvist, F. Disposition of chloroquine in man after single intravenous and oral doses. Br. J. Clin. Pharmacol. 1983, 15, 471–479.
  7. Frisk-Holmberg, M.; Bergqvist, Y.; Termond, E.; Domeij-Nyberg, B. The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects. Eur. J. Clin. Pharmacol. 1984, 26, 521–530.
  8. MacIntyre, A.C.; Cutler, D.J. The potential role of lysosomes in tissue distribution of weak bases. Biopharm. Drug Dispos. 1988, 9, 513–526.
  9. Veignie, E.; Moreau, S. The mode of action of chloroquine. Non-weak base properties of 4-aminoquinolines and antimalarial effects on strains ofPlasmodium. Ann. Trop. Med. Parasitol. 1991, 85, 229–237.
  10. Tett, S.; Cutler, D.; Day, R.; Brown, K. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br. J. Clin. Pharmacol. 1989, 27, 771–779.
  11. White, N.J.; Miller, K.D.; Churchill, F.C.; Berry, C.; Brown, J.; Williams, S.B.; Greenwood, B.M. Chloroqine Treatment of Severe Malaria in Children. Pharmacokinetics, toxicity, and new dosage recommendations. N. Engl. J. Med. 1988, 319, 1493–1500.
  12. Karunajeewa, H.A.; Salman, S.; Mueller, I.; Baiwog, F.; Gomorrai, S.; Law, I.; Page-Sharp, M.; Rogerson, S.; Siba, P.; Ilett, K.F.; et al. Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy. Antimicrob. Agents Chemother. 2010, 54, 1186–1192.
  13. Ofori-Adjei, D.; Ericsson, O.; Lindstrom, B.; Sjöqvist, F. Protein binding of chloroquine enantiomers and desethylchloroquine. Br. J. Clin. Pharmacol. 1986, 22, 356–358.
  14. Walker, O.; Birkett, D.; Alvan, G.; Gustafsson, L.; Sjoqvist, F. Characterization of chloroquine plasma protein binding in man. Br. J. Clin. Pharmacol. 1983, 15, 375–377.
  15. Augustijns, P.; Verbeke, N. Stereoselective Pharmacokinetic Properties of Chloroquine and De-Ethyl-Chloroquine in Humans. Clin. Pharmacokinet. 1993, 24, 259–269.
  16. Aderounmu, A.F.; Salako, L.A.; Lindstrom, B.; Walker, O.; Ekman, L. Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans. Br. J. Clin. Pharmacol. 1986, 22, 559–564.
  17. Ducharme, J.; Farinotti, R. Clinical Pharmacokinetics and Metabolism of Chloroquine. Focus on recent advancements. Clin. Pharmacokinet. 1996, 31, 257–274.
  18. Hansen, M.; Rubinsztein, D.C.; Walker, D.W. Autophagy as a promoter of longevity: Insights from model organisms. Nat. Rev. Mol. Cell Biol. 2018, 19, 579–593.
  19. Gómez, V.E.; Giovannetti, E.; Peters, G.J. Unraveling the complexity of autophagy: Potential therapeutic applications in Pancreatic Ductal Adenocarcinoma. Semin. Cancer Biol. 2015, 35, 11–19.
  20. Green, D.R.; Llambi, F. Cell death signaling. Cold Spring Harb. Perspect. Biol. 2015, 7, a006080.
  21. Boone, B.A.; Zeh, H.J.; Bahary, N. Autophagy Inhibition in Pancreatic Adenocarcinoma. Clin. Color. Cancer 2018, 17, 25–31.
  22. Thomé, R.; Lopes, S.C.P.; Costa, F.T.M.; Verinaud, L. Chloroquine: Modes of action of an undervalued drug. Immunol. Lett. 2013, 153, 50–57.
  23. Sundelin, S.P.; Terman, A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS 2002, 110, 481–489.
  24. Kang, R.; Tang, D. Autophagy in pancreatic cancer pathogenesis and treatment. Am. J. Cancer Res. 2012, 2, 383–396.
  25. Qureshi-Baig, K.; Kuhn, D.; Viry, E.; Pozdeev, V.I.; Schmitz, M.; Rodriguez, F.; Ullmann, P.; Koncina, E.; Nurmik, M.; Frasquilho, S.; et al. Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway. Autophagy 2020, 16, 1436–1452.
  26. Sehgal, A.R.; Konig, H.; Johnson, D.E.; Tang, D.; Amaravadi, R.K.; Boyiadzis, M.; Lotze, M.T. You eat what you are: Autophagy inhibition as a therapeutic strategy in leukemia. Leukemia 2015, 29, 517–525.
  27. Martinez-Outschoorn, U.; Pavlides, S.; Whitaker-Menezes, D.; Daumer, K.M.; Milliman, J.N.; Chiavarina, B.; Migneco, G.; Witkiewicz, A.K.; Cantarin, M.P.M.; Flomenberg, N.; et al. Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle 2010, 9, 2423–2433.
  28. Bigelsen, S. Evidence-based complementary treatment of pancreatic cancer: A review of adjunct therapies including paricalcitol, hydroxychloroquine, intravenous vitamin C, statins, metformin, curcumin, and aspirin. Cancer Manag. Res. 2018, 10, 2003–2018.
  29. Yang, S.; Wang, X.; Contino, G.; Liesa, M.; Sahin, E.; Ying, H.; Bause, A.; Li, Y.; Stommel, J.M.; Dell’Antonio, G.; et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011, 25, 717–729.
  30. Yang, M.-C.; Wang, H.-C.; Hou, Y.-C.; Tung, H.-L.; Chiu, T.-J.; Shan, Y.-S. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol. Cancer 2015, 14, 179.
  31. Bousquet, G.; El Bouchtaoui, M.; Sophie, T.; Leboeuf, C.; de Bazelaire, C.; Ratajczak, P.; Giacchetti, S.; de Roquancourt, A.; Bertheau, P.; Verneuil, L.; et al. Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer. Oncotarget 2017, 8, 35205.
  32. Li, Y.-J.; Lei, Y.-H.; Yao, N.; Wang, C.-R.; Hu, N.; Ye, W.-C.; Zhang, D.-M.; Chen, Z.-S. Autophagy and multidrug resistance in cancer. Chin. J. Cancer 2017, 36, 52.
  33. An, Y.; Zhang, Z.; Shang, Y.; Jiang, X.; Dong, J.; Yu, P.; Nie, Y.; Zhao, Q. miR-23b-3p regulates the chemoresistance of gastric cancer cells by targeting ATG12 and HMGB2. Cell Death Dis. 2015, 6, e1766.
  34. Hashimoto, D.; Bläuer, M.; Hirota, M.; Ikonen, N.H.; Sand, J.; Laukkarinen, J. Autophagy is needed for the growth of pancreatic adenocarcinoma and has a cytoprotective effect against anticancer drugs. Eur. J. Cancer 2014, 50, 1382–1390.
  35. Huang, H.; Song, J.; Liu, Z.; Pan, L.; Xu, G. Autophagy activation promotes bevacizumab resistance in glioblastoma by suppressing Akt/mTOR signaling pathway. Oncol. Lett. 2018, 15, 1487–1494.
  36. Liu, L.-Q.; Wang, S.-B.; Shao, Y.-F.; Shi, J.-N.; Wang, W.; Chen, W.-Y.; Ye, Z.-Q.; Jiang, J.-Y.; Fang, Q.-X.; Zhang, G.-B.; et al. Hydroxychloroquine potentiates the anti-cancer effect of bevacizumab on glioblastoma via the inhibition of autophagy. Biomed. Pharmacother. 2019, 118, 109339.
  37. Endo, S.; Nakata, K.; Ohuchida, K.; Takesue, S.; Nakayama, H.; Abe, T.; Koikawa, K.; Okumura, T.; Sada, M.; Horioka, K.; et al. Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated with Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice. Gastroenterology 2017, 152, 1492–1506.e24.
  38. Rockel, J.S.; Kapoor, J.S.R.M. Autophagy: Controlling cell fate in rheumatic diseases. Nat. Rev. Rheumatol. 2016, 12, 517–531.
  39. Delgado-Rizo, V.; Martínez-Guzmán, M.A.; Iñiguez-Gutierrez, L.; García-Orozco, A.; Alvarado-Navarro, A.; Fafutis-Morris, M. Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview. Front. Immunol. 2017, 8, 81.
  40. Schrezenmeier, E.; Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: Implications for rheumatology. Nat. Rev. Rheumatol. 2020, 16, 155–166.
  41. Khan, U.; Ghazanfar, H. T Lymphocytes and Autoimmunity. Int. Rev. Cell Mol. Biol. 2018, 341, 125–168.
  42. Serrano-Puebla, A.; Boya, P. Lysosomal membrane permeabilization as a cell death mechanism in cancer cells. Biochem. Soc. Trans. 2018, 46, 207–215.
  43. Boya, P.; Gonzalez-Polo, R.-A.; Poncet, D.; Andreau, K.; LA Vieira, H.; Roumier, T.; Perfettini, J.-L.; Kroemer, G. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003, 22, 3927–3936.
  44. Circu, M.; Cardelli, J.; Barr, M.; O’Byrne, K.; Mills, G.; El-Osta, H. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells. PLoS ONE 2017, 12, e0184922.
  45. Seitz, C.; Hugle, M.; Cristofanon, S.; Tchoghandjian, A.; Fulda, S. The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int. J. Cancer 2013, 132, 2682–2693.
  46. Enzenmüller, S.; Gonzalez, P.; Debatin, K.-M.; Fulda, S. Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K/mTOR inhibitor PI103 by lysosome-mediated apoptosis. Anti-Cancer Drugs 2013, 24, 14–19.
  47. Coban, C. The host targeting effect of chloroquine in malaria. Curr. Opin. Immunol. 2020, 66, 98–107.
  48. Wicht, K.J.; Mok, S.; Fidock, D.A. Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria. Annu. Rev. Microbiol. 2020, 74, 431–454.
  49. Fidock, D.A.; Nomura, T.; Talley, A.K.; Cooper, R.A.; Dzekunov, S.M.; Ferdig, M.T.; Ursos, L.M.; Sidhu, A.B.S.; Naudé, B.; Deitsch, K.W.; et al. Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance. Mol. Cell 2000, 6, 861–871.
  50. Savarino, A.; Gennero, L.; Chen, H.C.; Serrano, D.; Malavasi, F.; Boelaert, J.R.; Sperber, K. Anti-HIV effects of chloroquine: Mechanisms of inhibition and spectrum of activity. AIDS 2001, 15, 2221–2229.
  51. Akpovwa, H. Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity. Cell Biochem. Funct. 2016, 34, 191–196.
  52. Gonzalez-Dunia, D.; Cubitt, B.; de la Torre, J.C. Mechanism of Borna Disease Virus Entry into Cells. J. Virol. 1998, 72, 783–788.
  53. Ros, C.; Burckhardt, C.J.; Kempf, C. Cytoplasmic Trafficking of Minute Virus of Mice: Low-pH Requirement, Routing to Late Endosomes, and Proteasome Interaction. J. Virol. 2002, 76, 12634–12645.
  54. Zhang, S.; Yi, C.; Li, C.; Zhang, F.; Peng, J.; Wang, Q.; Liu, X.; Ye, X.; Li, P.; Wu, M.; et al. Chloroquine inhibits endosomal viral RNA release and autophagy-dependent viral replication and effectively prevents maternal to fetal transmission of Zika virus. Antivir. Res. 2019, 169, 104547.
  55. Bishop, N.E. Examination of Potential Inhibitors of Hepatitis A Virus Uncoating. Intervirology 1998, 41, 261–271.
  56. Jiang, M.-C.; Lin, J.-K.; Chen, S.S.-L. Inhibition of HIV-1 Tat-Mediated Transactivation by Quinacrine and Chloroquine. Biochem. Biophys. Res. Commun. 1996, 226, 1–7.
  57. Ahmad-Nejad, P.; Häcker, H.; Rutz, M.; Bauer, S.; Vabulas, R.M.; Wagner, H. Bacterial CpG-DNA and lipopolysaccharides activate toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 2002, 32, 1958–1968.
  58. Liu, Y.; Yan, W.; Tohme, S.; Chen, M.; Fu, Y.; Tian, D.; Lotze, M.; Tang, D.; Tsung, A. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J. Hepatol. 2015, 63, 114–121.
  59. Tian, J.; Avalos, A.M.; Mao, S.-Y.; Chen, B.; Senthil, K.; Wu, H.; Parroche, P.; Drabic, S.; Golenbock, D.T.; Sirois, C.M.; et al. Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 2007, 8, 487–496.
  60. Tai, N.; Wong, F.S.; Wen, L. The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes. J. Autoimmun. 2016, 71, 26–34.
  61. Tai, N.; Wong, F.S.; Wen, L. TLR9 Deficiency Promotes CD73 Expression in T Cells and Diabetes Protection in Nonobese Diabetic Mice. J. Immunol. 2013, 191, 2926–2937.
  62. Liu, M.; Peng, J.; Tai, N.; Pearson, J.A.; Hu, C.; Guo, J.; Hou, L.; Zhao, H.; Wong, F.S.; Wen, L. Toll-like receptor 9 negatively regulates pancreatic islet beta cell growth and function in a mouse model of type 1 diabetes. Diabetologia 2018, 61, 2333–2343.
  63. Rutz, M.; Metzger, J.; Gellert, T.; Luppa, P.; Lipford, G.B.; Wagner, H.; Bauer, S. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Eur. J. Immunol. 2004, 34, 2541–2550.
  64. Yasuda, H.; Leelahavanichkul, A.; Tsunoda, S.; Dear, J.W.; Takahashi, Y.; Ito, S.; Hu, X.; Zhou, H.; Doi, K.; Childs, R.; et al. Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am. J. Physiol. Physiol. 2008, 294, F1050–F1058.
  65. El Kebir, D.; József, L.; Pan, W.; Wang, L.; Filep, J.G. Bacterial DNA Activates Endothelial Cells and Promotes Neutrophil Adherence through TLR9 Signaling. J. Immunol. 2009, 182, 4386–4394.
  66. Sacre, K.; Criswell, L.A.; McCune, J.M. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res. Ther. 2012, 14, R155.
  67. Kužnik, A.; Benčina, M.; Švajger, U.; Jeras, M.; Rozman, B.; Jerala, R. Mechanism of Endosomal TLR Inhibition by Antimalarial Drugs and Imidazoquinolines. J. Immunol. 2011, 186, 4794–4804.
  68. Zhang, S.; Zhang, Q.; Wang, F.; Guo, X.; Liu, T.; Zhao, Y.; Gu, B.; Chen, H.; Li, Y. Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice. Clin. Immunol. 2020, 216, 108461.
  69. Zhou, W.; Guo, S.; Liu, M.; Burow, M.E.; Wang, G. Targeting CXCL12/CXCR4 Axis in Tumor Immunotherapy. Curr. Med. Chem. 2019, 26, 3026–3041.
  70. Pozzobon, T.; Goldoni, G.; Viola, A.; Molon, B. CXCR4 signaling in health and disease. Immunol. Lett. 2016, 177, 6–15.
  71. Tachibana, K.; Hirota, S.; Iizasa, H.; Yoshida, H.; Kawabata, K.; Kataoka, Y.; Kitamura, Y.; Matsushima, K.; Yoshida, N.; Nishikawa, S.-I.; et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 1998, 393, 591–594.
  72. Nagasawa, T.; Hirota, S.; Tachibana, K.; Takakura, N.; Nishikawa, S.-I.; Kitamura, Y.; Yoshida, N.; Kikutani, H.; Kishimoto, T. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 1996, 382, 635–638.
  73. Kruizinga, R.C.; Bestebroer, J.; Berghuis, P.; de Haas, C.J.C.; Links, T.P.; de Vries, E.G.E.; Walenkamp, A.M.E. Role of chemokines and their receptors in cancer. Curr. Pharm. Des. 2009, 15, 3396–3416.
  74. Domańska, U.M.; Kruizinga, R.C.; Nagengast, W.B.; Timmer-Bosscha, H.; Huls, G.; de Vries, E.G.; Walenkamp, A.M. A review on CXCR4/CXCL12 axis in oncology: No place to hide. Eur. J. Cancer 2013, 49, 219–230.
  75. Feng, Y.; Broder, C.C.; Kennedy, P.E.; Berger, E.A. HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor. Science 1996, 272, 872–877.
  76. Loetscher, P.; Moser, B.; Baggiolini, M. Chemokines and Their Receptors in Lymphocyte Traffic and HIV Infection. Adv. Immunol. 2000, 74, 127–180.
  77. Mortezaee, K. CXCL12/CXCR4 axis in the microenvironment of solid tumors: A critical mediator of metastasis. Life Sci. 2020, 249, 117534.
  78. Mousavi, A. CXCL12/CXCR4 signal transduction in diseases and its molecular approaches in targeted-therapy. Immunol. Lett. 2020, 217, 91–115.
  79. Chatterjee, S.; Azad, B.B.; Nimmagadda, S. The Intricate Role of CXCR4 in Cancer. Adv. Cancer Res. 2014, 124, 31–82.
  80. Han, J.; Li, X.; Luo, X.; He, J.; Huang, X.; Zhou, Q.; Han, Y.; Jie, H.; Zhuang, J.; Li, Y.; et al. The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling. Biomed. Pharmacother. 2020, 132, 110848.
  81. Schols, D.; Hatse, S. CXCL12-CXCR4 Axis in Angiogenesis, Metastasis and Stem Cell Mobilization. Curr. Pharm. Des. 2010, 16, 3903–3920.
  82. Kim, J.; Yip, M.L.R.; Shen, X.; Li, H.; Hsin, L.-Y.C.; LaBarge, S.; Heinrich, E.L.; Lee, W.; Lu, J.; Vaidehi, N. Identification of Anti-Malarial Compounds as Novel Antagonists to Chemokine Receptor CXCR4 in Pancreatic Cancer Cells. PLoS ONE 2012, 7, e31004.
  83. Balic, A.; Sørensen, M.D.; Trabulo, S.M.; Sainz, B.; Cioffi, M.; Vieira, C.R.; Miranda-Lorenzo, I.; Hidalgo, M.; Kleeff, J.; Erkan, M.; et al. Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling. Mol. Cancer Ther. 2014, 13, 1758–1771.
  84. Yue, D.; Zhang, D.; Shi, X.; Liu, S.; Li, A.; Wang, D.; Qin, G.; Ping, Y.; Qiao, Y.; Chen, X.; et al. Chloroquine Inhibits Stemness of Esophageal Squamous Cell Carcinoma Cells Through Targeting CXCR4-STAT3 Pathway. Front. Oncol. 2020, 10, 311.
  85. Verbaanderd, C.; Maes, H.; Schaaf, M.B.; Sukhatme, V.P.; Pantziarka, P.; Sukhatme, V.; Agostinis, P.; Bouche, G. Repurposing Drugs in Oncology (ReDO)—Chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience 2017, 11, 781.
  86. Yu, F.; Xie, Y.; Wang, Y.; Peng, Z.-H.; Li, J.; Oupický, D. Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis. ACS Macro Lett. 2016, 5, 342–345.
  87. Yu, F.; Li, J.; Xie, Y.; Sleightholm, R.L.; Oupický, D. Polymeric chloroquine as an inhibitor of cancer cell migration and experimental lung metastasis. J. Control. Release 2016, 244, 347–356.
  88. Kang, R.; Zeh, H.J.; Lotze, M.T.; Tang, D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011, 18, 571–580.
  89. Xu, T.; Jiang, L.; Wang, Z. The progression of HMGB1-induced autophagy in cancer biology. OncoTargets Ther. 2019, 12, 365–377.
  90. Schiraldi, M.; Raucci, A.; Muñoz, L.M.; Livoti, E.; Celona, B.; Venereau, E.; Apuzzo, T.; De Marchis, F.; Pedotti, M.; Bachi, A.; et al. HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J. Exp. Med. 2012, 209, 551–563.
  91. Yasinska, I.; Silva, I.G.; Sakhnevych, S.S.; Ruegg, L.; Hussain, R.; Siligardi, G.; Fiedler, W.; Wellbrock, J.; Bardelli, M.; Varani, L.; et al. High mobility group box 1 (HMGB1) acts as an “alarmin” to promote acute myeloid leukaemia progression. OncoImmunology 2018, 7, e1438109.
  92. Yang, M.; Cao, L.; Xie, M.; Yu, Y.; Kang, R.; Yang, L.; Zhao, M.; Tang, D. Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis. Biochem. Pharmacol. 2013, 86, 410–418.
  93. Chiba, S.; Baghdadi, M.; Akiba, H.; Yoshiyama, H.; Kinoshita, I.; Dosaka-Akita, H.; Fujioka, Y.; Ohba, Y.; Gorman, J.V.; Colgan, J.D.; et al. Tumor-infiltrating DCs suppress nucleic acid–mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 2012, 13, 832–842.
  94. Zhang, Y.-P.; Cui, Q.-Y.; Zhang, T.-M.; Yi, Y.; Nie, J.-J.; Xie, G.-H.; Wu, J.-H. Chloroquine pretreatment attenuates ischemia-reperfusion injury in the brain of ob/ob diabetic mice as well as wildtype mice. Brain Res. 2020, 1726, 146518.
  95. Dai, C.; Xiao, X.; Li, D.; Tun, S.; Wang, Y.; Velkov, T.; Tang, S. Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis. Cell Death Dis. 2018, 9, 1164.
  96. Schierbeck, H.; Wähämaa, H.; Andersson, U.; Harris, H.E. Immunomodulatory Drugs Regulate HMGB1 Release from Activated Human Monocytes. Mol. Med. 2010, 16, 343–351.
  97. Nosál’, R.; Jančinová, V.; Danihelová, E. Chloroquine: A Multipotent Inhibitor of Human Platelets In Vitro. Thromb. Res. 2000, 98, 411–421.
  98. Nosál’, R.; Jančinová, V. Cationic amphiphilic drugs and platelet phospholipase A2 (cPLA2). Thromb. Res. 2002, 105, 339–345.
  99. Nosál, R.; Jančinová, V.; Petríková, M. Chloroquine inhibits stimulated platelets at the arachidonic acid pathway. Thromb. Res. 1995, 77, 531–542.
  100. Li, P.; Li, M.; Lindberg, M.R.; Kennett, M.J.; Xiong, N.; Wang, Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 2010, 207, 1853–1862.
  101. Lewis, H.D.; Liddle, J.; Coote, J.E.; Atkinson, S.J.; Barker, M.D.; Bax, B.; Bicker, K.L.; Bingham, R.P.; Campbell, M.; Chen, Y.H.; et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat. Chem. Biol. 2015, 11, 189–191.
  102. Petri, M. Use of Hydroxychloroquine to Prevent Thrombosis in Systemic Lupus Erythematosus and in Antiphospholipid Antibody–Positive Patients. Curr. Rheumatol. Rep. 2010, 13, 77–80.
  103. Tektonidou, M.G.; Tincani, A.; Ward, M.M. Response to: “Correspondence on EULAR recommendations for the management of antiphospholipid syndrome in adults” by Gao and Qin. Ann. Rheum. Dis. 2021.
  104. Rand, J.H.; Wu, X.-X.; Quinn, A.S.; Ashton, A.W.; Chen, P.P.; Hathcock, J.J.; Andree, H.A.M.; Taatjes, D.J. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: Evidence for a novel effect for an old antimalarial drug. Blood 2010, 115, 2292–2299.
  105. Espinola, R.G.; Pierangeli, S.S.; Ghara, A.E.; Harris, E.N. Hydroxychloroquine reverses platelet acti-vation induced by human IgG antiphospholipid antibodies. Thromb. Haemost. 2002, 87, 518–522.
  106. Edwards, M.H.; Pierangeli, S.; Liu, X.; Barker, J.H.; Anderson, G.; Harris, E.N. Hydroxychloroquine Reverses Thrombogenic Properties of Antiphospholipid Antibodies in Mice. Circulation 1997, 96, 4380–4384.
  107. Miranda, S.; Billoir, P.; Damian, L.; Thiebaut, P.A.; Schapman, D.; Le Besnerais, M.; Jouen, F.; Galas, L.; Levesque, H.; Le Cam-Duchez, V.; et al. Hydroxychloroquine reverses the prothrombotic state in a mouse model of antiphospholipid syndrome: Role of reduced inflammation and endothelial dysfunction. PLoS ONE 2019, 14, e0212614.
  108. Urbanski, G.; Caillon, A.; Poli, C.; Kauffenstein, G.; Begorre, M.-A.; Loufrani, L.; Henrion, D.; Belizna, C. Hydroxychloroquine partially prevents endothelial dysfunction induced by anti-beta-2-GPI antibodies in an in vivo mouse model of antiphospholipid syndrome. PLoS ONE 2018, 13, e0206814.
  109. Pierangeli, S.S.; Vega-Ostertag, M.; Harris, E.N. Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: A pathway to targeted therapies. Thromb. Res. 2004, 114, 467–476.
  110. Rand, J.H.; Wu, X.-X.; Quinn, A.S.; Chen, P.P.; Hathcock, J.J.; Taatjes, D.J. Hydroxychloroquine directly reduces the binding of antiphospholipid antibody–β2-glycoprotein I complexes to phospholipid bilayers. Blood 2008, 112, 1687–1695.
  111. Müller-Calleja, N.; Hollerbach, A.; Häuser, F.; Canisius, A.; Orning, C.; Lackner, K.J. Antiphospholipid antibody-induced cellular responses depend on epitope specificity: Implications for treatment of antiphospholipid syndrome. J. Thromb. Haemost. 2017, 15, 2367–2376.
  112. Müller-Calleja, N.; Manukyan, D.; Canisius, A.; Strand, D.; Lackner, K.J. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann. Rheum. Dis. 2017, 76, 891–897.
  113. De Moreuil, C.; Alavi, Z.; Pasquier, E. Hydroxychloroquine may be beneficial in preeclampsia and recurrent miscarriage. Br. J. Clin. Pharmacol. 2020, 86, 39–49.
  114. Josephs, S.F.; Ichim, T.E.; Prince, S.M.; Kesari, S.; Marincola, F.M.; Escobedo, A.R.; Jafri, A. Unleashing endogenous TNF-alpha as a cancer immunotherapeutic. J. Transl. Med. 2018, 16, 242.
  115. Le, N.-T.; Takei, Y.; Izawa-Ishizawa, Y.; Heo, K.-S.; Lee, H.; Smrcka, A.V.; Miller, B.; Ko, K.A.; Ture, S.; Morrell, C.; et al. Identification of Activators of ERK5 Transcriptional Activity by High-Throughput Screening and the Role of Endothelial ERK5 in Vasoprotective Effects Induced by Statins and Antimalarial Agents. J. Immunol. 2014, 193, 3803–3815.
  116. Dyer, M.R.; Alexander, W.; Hassoune, A.; Chen, Q.; Brzoska, T.; Alvikas, J.; Liu, Y.; Haldeman, S.; Plautz, W.; Loughran, P.; et al. Platelet-derived extracellular vesicles released after trauma promote hemostasis and contribute to DVT in mice. J. Thromb. Haemost. 2019, 17, 1733–1745.
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , ,
View Times: 299
Revisions: 2 times (View History)
Update Date: 09 Dec 2022
Video Production Service