Next Article in Journal / Special Issue
Macrophage Delivered HSV1716 Is Active against Triple Negative Breast Cancer
Previous Article in Journal / Special Issue
Dendrimers-Based Drug Delivery System: A Novel Approach in Addressing Parkinson’s Disease
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer

Amal Kamal Abdel-Aziz
Mona Kamal Saadeldin
Ahmed Hamed Salem
Safaa A. Ibrahim
Samia Shouman
Ashraf B. Abdel-Naim
10 and
Roberto Orecchia
Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
KAUST Smart-Health Initiative and Biological and Environmental Science and Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Jeddah 23955, Saudi Arabia
Electrical Engineering and Biological Sciences Departments, University of Notre Dame, Notre Dame, IN 46556, USA
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
Department of Microbiology and Immunology, Chicago Medical School, North Chicago, IL 60064, USA
Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Scientific Directorate, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
Author to whom correspondence should be addressed.
Future Pharmacol. 2022, 2(4), 431-443;
Submission received: 27 September 2022 / Revised: 13 October 2022 / Accepted: 13 October 2022 / Published: 18 October 2022
(This article belongs to the Special Issue Feature Papers in Future Pharmacology)


Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used to treat malaria and autoimmune diseases for more than 70 years; they also have immunomodulatory and anticancer effects, which are linked to autophagy and autophagy-independent mechanisms. Herein, we review the pharmacokinetics, preclinical studies and clinical trials investigating the use of CQ and HCQ as adjuvant agents in cancer therapy. We also discuss their safety profile, drug–drug and drug–disease interactions. Systematic studies are required to define the use of CQ/HCQ and/or their analogues in cancer treatment and to identify predictive biomarkers of responder subpopulations.

1. Introduction

In 1930, quinacrine (an acridine derivative) was introduced for treating malaria [1]. Its toxicity and limited efficacy stimulated the synthesis of chloroquine (CQ) in which the acridine ring of quinacrine was replaced with a quinoline ring [2]. Repurposing the use of CQ for treating patients with autoimmune diseases stemmed—at least partially—from observations during World War II that cutaneous rashes and arthritis improved in soldiers who received CQ and quinacrine as prophylaxis against malaria [2]. Hydroxychloroquine (HCQ) was synthesized later and, owing to its favorable safety profile compared to CQ [3], HCQ has been used for decades in the treatment of autoimmune diseases as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [2,4].
There is at least preclinical evidence that CQ and HCQ have anticancer activity. Below, we discuss their pharmacokinetics and the preclinical studies and clinical trials investigating the use of CQ or HCQ in cancer therapy.

2. Pharmacokinetics

Chloroquine and HCQ are well-absorbed orally, reaching peak plasma levels within 2–4.5 h [5,6,7]. In plasma, 30–40% are bound to albumin and α1-acid glycoprotein [6].Their stereoisomers exhibit differential binding, metabolism and activity [2,6].
Chloroquine and HCQ can bind to melanin in pigmented tissues, mononuclear cells and muscles [2,6]. During prolonged treatment, they accumulate with higher concentration in the heart, liver, brain, muscle and skin than in blood and their tissue concentration may correlate better with their efficacy than their blood levels [2,7].
In the liver, CQ is de-alkylated via cytochrome P450 (mainly CYP3A, CYP2C8 and CYP2D6) into the pharmacologically active desethyl CQ and bisdesethyl CQ metabolites [8,9]. HCQ is metabolized via CYP3A4 driven dealkylation into three active metabolites: desethyl CQ, desethyl HCQ and bisdesethyl HCQ [10]. Almost 40–50% of CQ and HCQ are excreted via the kidneys [6]. Being amphiphilic weak bases, CQ and HCQ are partially protonated at physiological pH (7.4) and biprotonated at acidic pH (4–5). Alkalinisation increases and acidification decreases the renal excretion of CQ [1]. CQ and HCQ have long terminal elimination half-lives (~40–50 days) [6,7].

3. Preclinical Studies of Anticancer Activity of CQ and HCQ

Several studies have described the anticancer potential of CQ and HCQ when used with standard cancer therapy [4,11,12,13]. CQ and HCQ elicit direct and indirect effects on cancer cells [12,13,14,15,16]. One mechanism of action is the inhibition of autophagy [2,4,11,12]. Autophagy (or self-eating) is a double-edged process, which can promote either cancer cell survival or death [17,18]. As an adaptive mechanism, some cancer cells exploit autophagy to survive during stressful conditions, such as nutrient deprivation, hypoxia or cytotoxic insults triggered by cancer therapy [11,12,19,20,21]. Mimicking tumor microenvironment by co-culturing cancer cells with fibroblasts promotes autophagy [22]. Conversely, the excessive induction of autophagy by diverse anticancer drugs has been reported to trigger autophagic cell death (or programmed cell death type II) of cancer cells [23,24,25]. CQ and HCQ act at the late stages of autophagy by raising lysosomal pH, which inhibits the fusion between autophagosomes and lysosomes, and thereby impairs lysosomal protein degradation [4,12]. Palmitoyl-protein thioesterase 1 has been identified as the lysosomal target of CQ/HCQ [26]. It is worth mentioning that the synergistic anticancer activity of CQ and temozolomide combination was abrogated with the pharmacological or genetic inhibition of early stages of autophagy [27]. Knocking down p53 or overexpressing mutant p53 also compromised the anticancer potential of CQ-temozolomide combination [27]. Notably, superior anticancer efficacy of CQ and erlotinib combination was maintained in the preclinical “cancer cells/fibroblasts co-culturing” setting, mimicking the tumor microenvironment [22]. Given the regulatory crosstalk between autophagy and apoptosis, the augmentation of the anticancer efficacy of chemotherapy by CQ or HCQ might be associated with increased apoptosis [12,14]. Indeed, the anti-apoptotic Bcl-2 family members as Bcl-2 and Bcl-xl inhibit autophagy [28]. CQ augmented the anticancer activity of Bcl-2 inhibitors [29,30]. The overexpression of Bcl-2 or Bcl-xL compromised apoptotic cancer cell death triggered in ABT-737 (Bcl-2 inhibitor), CQ and their combination [30].
The physicochemical properties of CQ and HCQ present a critical limitation that restrains their anticancer activity [31]. Solid tumours often develop an insufficient vasculature to supply their nutrient needs and contain regions of hypoxia. Hypoxic cancer cells depend on glycolysis, and other cancer cells may use glycolysis electively for ATP synthesis. This promotes an acidic extracellular microenvironments, which compromises the cellular uptake of CQ/HCQ [31]. To overcome this shortcoming, a series of CQ/HCQ derivatives has been synthesized to increase their anticancer potential [31,32,33,34,35]. For instance, Lys05, a dimeric CQ, has been reported to be a more potent inhibitor of autophagy with greater anticancer activity than HCQ [34,35]. However, chronic daily treatment of mice with Lys05 was associated with Paneth cell dysfunction, although without obvious signs of gastrointestinal toxicity [35]. Since inhibitors of autophagy have been shown to improve the effects of chemotherapy in preclinical models, they should undergo clinical evaluation.
CRISPR-Cas9 loss-of-function screening identified insulin-like growth factor 1 receptor (IGF1R) as a sensitizer of pancreatic ductal adenocarcinoma cells to CQ/HCQ [36]. Co-targeting IGF1R and ERK inhibited glycolysis and augmented the dependence of pancreatic ductal adenocarcinoma cells on autophagy, and hence rendered them more vulnerable to CQ/HCQ [36].
Chloroquine has also been reported to augment the vulnerability of cancer cells to chemotherapy via autophagy-independent mechanisms, including the normalization of tumour vasculature, which decreases intratumoral hypoxia, cancer cell invasion and metastasis [37,38]. Notably, CQ-induced vessel normalization was linked to activated endothelial Notch1 signaling [39,40]. CQ also sensitized triple negative breast cancer cells to paclitaxel via reducing CD44+/CD24−/low cancer stem cells [41].
Chloroquine and HCQ have been reported to inhibit angiogenesis [12]; they also induced the secretion of the tumour suppressor prostate apoptosis response-4 (Par-4) from normal cells of treated mice and cancer patients, which triggered paracrine apoptosis of cancer cells and inhibited tumour metastasis [16]. Furthermore, CQ promoted the anti-tumour immune responses via resetting tumour-associated macrophages from the M2 to the tumour-killing M1 phenotype [15]. CQ increases macrophage lysosomal pH and triggers Ca2+ release through the lysosomal Ca2+ channel mucolipin-1, which activates p38 and nuclear factor kappa B (NF-κB), thereby causing tumour-associated macrophages to adopt an M1 phenotype [15]. The antitumor immune responses provoked by CQ were observed preclinically when used at relatively high concentration (10 μM). However, the safe plasma level/concentration of CQ is reported to be approximately 3 μM [42] so that the antitumor immunogenic doses of CQ might not be tolerable clinically. The limited clinical efficacy of immune checkpoint inhibitors as monotherapy has instigated the investigating of its inclusion in diverse combinatorial regimens [43,44]. Of note, HCQ compromised the anticancer T cell immune responses triggered by anti-PD1 in syngeneic tumor mouse models [45]. Thus, caution is warranted, since prolonged exposure to clinically approved doses of CQ and HCQ may suppress immune responses, as occurs during their use in treating autoimmune diseases [2].

4. Dose and Schedule

To optimize the dose and schedule of CQ/HCQ, their target therapeutic concentrations must be identified. Three strategies might be used to achieve this objective: (i) Use of in vitro models to evaluate the pharmacodynamics (PD) of CQ and HCQ against cancer cells. In simple models, cancer cells are exposed to constant concentrations of the agent, but to better understand the impact of the pharmacokinetic (PK) profile on anticancer activity, dynamic in vitro models can be used to expose cancer cells to fluctuating concentrations of CQ and HCQ. (ii) Use of animal models, which better mimic the PK profile and immune system in people. Such models also allow dose fractionation studies to better understand the interplay between PK and PD. (iii) Use of clinical data to determine the dose and schedule that show the best correlation with the anticancer activity of these agents. This would require the use of different dosage regimens for CQ and HCQ and assessment of their plasma concentrations. In comparing CQ and HCQ, it is critical to account for the protein binding of both agents, since only free drug is pharmacologically active.
Once the therapeutic target concentrations for CQ and HCQ have been estimated, a population PK model can be used to estimate their concentrations for different doses and schedules. These models already exist for CQ and HCQ, based on data from patients with malaria, RA or SLE [46,47,48]. In Japanese subjects, weight was found to influence HCQ PK; therefore, weight based dosage regimens of HCQ should be considered [46]. Assuming cancer has no impact on the PK of CQ and HCQ, these models can be used to optimize the dose and schedule of CQ and HCQ in cancer patients. Coupling PK/PD models with Monte Carlo simulation [49,50] could be utilized to compare the anticancer efficacies of different doses of CQ and HCQ.

5. Safety Profile

Chloroquine and HCQ have some adverse effects, associated especially with their long-term use [5,51]. Cardiac disorders have been reported in patients treated for a median of 7 years [range:3 days–35 years] with a high cumulative dose (median 800 g CQ or 1235 g HCQ) [51]. Among the cardiotoxic effects associated with their use is bundle or atrio-ventricular block, prolonged QT interval and Torsade de Pointes (TdP) [5,51]. The risk factors for developing TdP include female gender, age (>65 years), history of drug-induced TdP, chronic renal or hepatic insufficiency, electrolyte abnormalities, diuretics and simultaneous use of QT-prolonging drugs [52]. Approximately half of the patients who discontinued treatment recovered normal heart function, but the remaining patients either suffered from irreversible cardiac damage or died (24 of 127) [51]. For cancer treatment, the drugs would usually be administered for a shorter period, typically one year or less, but patients should be checked for cardiac toxicity and treatment should be withdrawn if cardiac manifestations are present.
Retinopathy is associated more frequently with CQ than HCQ [3,5,51]. CQ and HCQ bind to melanin and inhibit the lysosomal activity in the retinal pigment epithelium (RPE), and hence reduce the phagocytosis of shed photoreceptor outer segments (shed rod and cone debris), resulting in their accumulation and damage of the macular cones outside of the fovea. RPE cells, thus, migrate into the outer nuclear and plexiform layers of the retina, resulting in irreversible photoreceptor loss and RPE atrophy [53]. A retrospective case series of patients with NSCLC who received HCQ (1000 mg/day) together with erlotinib reported that two of seven patients who had been treated for ≥6 months developed retinal toxicity—without symptomatic visual acuity loss—at 11 and 17 months of exposure. Although fundus autofluorescence imaging was normal, the retinal damage was identified by optical coherence tomography and multifocal electroretinography testing [54]. Thus, long-term use of HCQ (1000 mg/day) may incite retinal toxicity within 1–2 years and sensitive retinal screening tests are needed [54].
Besides its role in cancer, autophagy plays a homeostatic role in normal cells, including heart, kidney and liver [55]. Preclinical studies have demonstrated that autophagy protects against cisplatin-induced acute nephrotoxicity and inhibiting autophagy using CQ exacerbates cisplatin-induced acute kidney damage [55]. Thus, monitoring the function of vital organs during therapy is essential.
Although the anti-malarial doses of CQ and HCQ are generally considered safe during pregnancy and breastfeeding, the safety of long-term use of higher doses for treating SLE and RA in pregnant or breastfeeding women is controversial [5,56,57].
Acute CQ poisoning (oral doses ≥ 50 mg/kg) can be lethal [5]. Intoxicated patients present with nausea and vomiting followed by slurred speech, agitation, breathlessness owing to pulmonary oedema, convulsions, arrhythmia and coma [5]. Quinidine-like cardiotoxicity has been reported following acute CQ poisoning. CQ blocks the rapid component of the delayed rectifying outward potassium current I, sodium and calcium channels, which leads to membrane-stabilization effects (resulting in AV block, QRS interval widening and QT prolongation), negative inotropic effects and peripheral vasodilatation [51,58]. The management of intoxicated cases within the first hours of CQ ingestion comprises prevention of further absorption. Otherwise, symptomatic treatment is required to maintain cardiac and respiratory functions. Diazepam can be used to control convulsions [5].

6. Clinical Trials

Several Phase I/II trials have evaluated the safety and efficacy of CQ and HCQ as monotherapy or in combination with surgery, radiotherapy or chemotherapy in treating patients with solid and hematological tumours (Table 1) [2,59,60,61,62,63,64,65,66,67]. Long-term treatment with HCQ (600 mg BID: the highest FDA-recommended dose) appears to be well-tolerated when given with anticancer therapy [61,66,67,68,69]. CQ and HCQ have negligible anticancer efficacy when used alone [60,70], but their long-term use in pre- and post-operative cancer patients has been associated with favorable clinical outcomes [61,64,65].
A meta-analysis of seven trials evaluating the addition of CQ or HCQ to standard cancer therapy (chemotherapy or radiation) in different types of cancer (glioblastoma, brain metastases from non-small cell lung cancer (NSCLC) and breast cancer, non-Hodgkin lymphoma and pancreatic adenocarcinoma) concluded that their use was associated with improvements in overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) [71]. Subgroup analysis revealed that CQ/HCQ-based therapy led to an improved 6-month PFS and 1-year OS in patients with glioblastoma, and to a higher ORR in patients with non-Hodgkin lymphoma. However, no significant improvement of ORR and 6-month PFS was found in patients with NSCLC or breast cancer. This meta-analysis has several limitations, since it included clinical studies that reported the effects of different treatment schedules of HCQ or CQ in different types of cancer, and did not provide information about long-term outcomes or the safety of the combination regimens [71].
A phase II randomized clinical trial (NCT01506973) has reported that adding HCQ to standard chemotherapy (gemcitabine and nab-paclitaxel) did not improve OS in patients with metastatic pancreatic adenocarcinoma [72]. Nonetheless, the ORR was significantly higher in the HCQ group, with a trend toward improved PFS, suggesting that a subpopulation of patients may benefit from the addition of HCQ. Another randomized clinical trial (NCT01978184) has revealed that preoperative addition of HCQ to gemcitabine and nab-paclitaxel resulted in better pathologic responses in patients with resectable pancreatic adenocarcinoma [61].
There are currently no sensitive and reliable predictive biomarkers that could guide clinicians towards the rational selection of cancer patients who could most likely benefit from CQ/HCQ. However, some studies suggested a handful of biomarkers in a limited number of patients, which warrant their further validation in clinical trials with larger cohorts [69,73,74]. Indeed, Fei and colleagues have retrospectively analyzed SMAD4 expression in pancreatic adenocarcinoma specimens of patients who were enrolled in two clinical trials (NCT01128296 and NCT01978184) evaluating the addition of pre-operative HCQ to neoadjuvant chemotherapy. The addition of HCQ was associated with better histopathologic response in pancreatic adenocarcinoma patients with SMAD4 loss [73]. There was a trend toward improved median OS—despite being statistically insignificant—in HCQ-treated patients with SMAD4 loss [73]. However, the results of this study should be interpreted with caution given its retrospective nature with data gathered from two clinical trials investigating different chemotherapy regimens. Prolonged disease-free survival and OS have been observed in pancreatic adenocarcinoma patients with > 51% increment in the peripheral blood levels of LC3-II—microtubule-associated proteins 1A/1B light chain 3B, which is used as an autophagic marker [69]. Conversely, p53 status did not correlate with the clinical outcome [69]. Elevated plasma levels of Par-4—but not tumor levels of sequestosome-1/p62 (which is used as a marker of inhibition of autophagic flux)—correlated with induced apoptosis in the tumor specimens of HCQ-treated patients [75].

7. Drug-Drug and Drug-Disease Interactions

Chloroquine and HCQ interact with several drugs, yet the molecular basis and magnitude/incidence for many remain unknown (Table 2). Some of these PK drug–drug interactions might be attributed to the modulatory effects of CQ/HCQ on the activity of some cytochrome P450 (CYP) metabolizing enzymes and/or p-glycoprotein [9,80,81,82].
Pharmacodynamic drug–drug interactions of CQ/HCQ with other QT prolonging drugs could increase the risk for developing TdP. Some anticancer drugs (such as sunitinib, cabozantinib and lapatinib) are associated with QT prolongation [52] and should not be used in combination with CQ or HCQ. Nausea and vomiting, which are frequently associated with anticancer therapy, may lead to dehydration followed by electrolyte imbalance, and thus provoke QT prolongation [52]. QT prolongation by some drugs is associated with increased incidence of arrhythmic death [52]. Using CQ or HCQ alone or with QT-prolonging anticancer drugs mandates careful cardiac monitoring and correction of any electrolyte abnormalities. The management of potentially fatal arrhythmias associated with prolonged QT syndrome involves the intravenous administration of magnesium sulphate and electrical cardioversion [52].
Tamoxifen decreases the activity of cathepsin D, a lysosomal acid protease, in the lysosomes of RPE, which is essential for the phagocytosis of the ingested rod outer segments shed from photoreceptor cells [85]. Increased risk factors for retinopathy include co-treatment with tamoxifen and HCQ, >5 mg/kg/day HCQ, pre-existing maculopathy and renal insufficiency [56].
Glucose 6-phosphate dehydrogenase (G6PD) protects RBCs against oxidative stress, which is triggered by CQ [93].Thus, CQ may cause hemolysis in patients with G6PD deficiency [93]. CQ/HCQ may also increase the risk of convulsions in patients with epilepsy [94,95]. Their epileptogenic potential is linked to inhibition of GABA and the enhancement of dopaminergic neurotransmissions [94,95].

8. Conclusions and Future Perspectives

Critical appraisal of the challenges of using CQ and HCQ as adjuvant agents in cancer patients can be summarized as follows:
  • Despite their preclinical anticancer and safety profile, there are currently no sensitive and reliable predictive biomarkers for the rational selection of cancer patients who could benefit from the use of CQ/HCQ and avoid the exposure of non-responders to their adverse effects.
  • Consideration of the risk and benefit for CQ/HCQ in cancer patients must be individualized.
  • Some anticancer drugs and HCQ/CQ are associated with a prolonged QT interval. Given the multifactorial developmental nature of TdP, careful cardiac monitoring and correction of electrolyte imbalance are critical and treatment withdrawal is needed if cardiac manifestations arise.
  • Given the homeostatic role of autophagy, which is inhibited by HCQ/CQ, monitoring of vital organs is essential.
  • Long-term follow-up of treated patients for potential cardiovascular, renal and retinal toxicities is warranted.

Author Contributions

Conceptualization, A.K.A.-A.; methodology, A.K.A.-A., M.K.S., A.H.S., S.A.I., S.S., A.B.A.-N., R.O.; data curation, A.K.A.-A.; writing—original draft preparation, M.K.S., A.H.S., S.A.I., S.S., A.B.A.-N., R.O.; writing—review and editing. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


The authors would like to thank Ian Tannock and Houriya Elbarbary for the constructive feedback and critical discussions.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Tanenbaum, L.; Tuffanelli, D.L. Antimalarial agents. Chloroquine, hydroxychloroquine, and quinacrine. Arch. Dermatol. 1980, 116, 587–591. [Google Scholar] [CrossRef] [PubMed]
  2. Plantone, D.; Koudriavtseva, T. Current and Future Use of Chloroquine and Hydroxychloroquine in Infectious, Immune, Neoplastic, and Neurological Diseases: A Mini-Review. Clin. Drug Investig. 2018, 38, 653–671. [Google Scholar] [CrossRef] [PubMed]
  3. Finbloom, D.; Silver, K.; Newsome, D.; Gunkel, R. Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity. J. Rheumatol. 1985, 12, 692–694. [Google Scholar] [PubMed]
  4. Thomé, R.; Costa, S.; Lopes, P.; Trindade, F.; Costa, M.; Verinaud, L. Chloroquine: Modes of action of an undervalued drug. Immunol. Lett. 2013, 153, 50–57. [Google Scholar] [CrossRef]
  5. WHO. WHO Model Prescribing Information: Drugs used in Parasitic Diseases, 2nd ed.; World Health Organization: Geneva, Switzerland, 1995; pp. 1–146. [Google Scholar]
  6. Furst, D. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 1996, 5 (Suppl. 1), S11–S15. [Google Scholar] [CrossRef]
  7. Tett, S.; Cutler, D.; Day, R.; Brown, K. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br. J. Clin. Pharmacol. 1989, 27, 771–779. [Google Scholar] [CrossRef] [Green Version]
  8. Ducharme, J.; Farinotti, R. Clinical Pharmacokinetics and Metabolism of Chloroquine. Clin. Pharmacokinet. 2012, 31, 257–274. [Google Scholar] [CrossRef] [PubMed]
  9. Lewis, J.; Gregorian, T.; Assistant, B.; Mlis, I.P.; Librarian, H.S.; Goad, J. Drug interactions with antimalarial medications in older travelers: A clinical guide. J. Travel Med. 2020, 27, taz089. [Google Scholar] [CrossRef] [Green Version]
  10. Lim, H.; Im, J.; Cho, J.; Bae, K.; Klein, T.A.; Yeom, J.; Kim, T.; Choi, J.; Jang, I.; Park, J. Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in Chemoprophylaxis against Malaria Caused by Plasmodium vivax. Antimicrob. Agents Chemother. 2009, 53, 1468–1475. [Google Scholar] [CrossRef] [Green Version]
  11. Sasaki, K.; Tsuno, N.H.; Sunami, E.; Tsurita, G.; Kawai, K.; Okaji, Y.; Nishikawa, T.; Shuno, Y.; Hongo, K.; Hiyoshi, M.; et al. Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer 2010, 10, 370. [Google Scholar] [CrossRef]
  12. Abdel-Aziz, A.K.; Shouman, S.; El-Demerdash, E.; Elgendy, M.; Abdel-Naim, A.B. Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries. Chem. Biol. Interact. 2014, 217, 28–40. [Google Scholar] [CrossRef] [PubMed]
  13. Abdel-Aziz, A.K.; Shouman, S.; El-Demerdash, E.; Elgendy, M.; Abdel-naim, A.B. Chloroquine as a promising adjuvant chemotherapy together with sunitinib. Sci. Proc. 2014, 1, 1–3. [Google Scholar]
  14. Monma, H.; Iida, Y.; Moritani, T.; Okimoto, T.; Tanino, R.; Tajima, Y.; Harada, M. Chloroquine augments TRAIL-induced apoptosis and induces G2/M phase arrest in human pancreatic cancer cells. PLoS ONE 2018, 13, e0193990. [Google Scholar] [CrossRef] [Green Version]
  15. Chen, D.; Xie, J.; Fiskesund, R.; Dong, W.; Liang, X.; Lv, J.; Jin, X.; Liu, J.; Mo, S.; Zhang, T.; et al. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. Nat. Commun. 2018, 9, 873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Burikhanov, R.; Hebbar, N.; Noothi, S.K.; Shukla, N.; Sledziona, J.; Araujo, N.; Kudrimoti, M.; Wang, Q.J.; Watt, D.S.; Welch, D.R.; et al. Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis. Cell Rep. 2017, 18, 508–519. [Google Scholar] [CrossRef]
  17. Maiuri, M.C.; Zalckvar, E.; Kimchi, A.; Kroemer, G. Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Mol. Cell Biol. 2007, 8, 741–752. [Google Scholar] [CrossRef]
  18. Abdel-aziz, A.K.; Abdel-naim, A.B.; Shouman, S.; Minucci, S. From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib. Front. Pharmacol. 2017, 8, 718. [Google Scholar] [CrossRef] [Green Version]
  19. Tan, Q.; Wang, M.; Yu, M.; Zhang, J.; Bristow, R.G.; Hill, R.P.; Tannock, I.F. Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors. Neoplasia 2016, 18, 347–355. [Google Scholar] [CrossRef]
  20. Tan, Q.; Joshua, A.M.; Wang, M.; Bristow, R.G.; Wouters, B.G.; Allen, C.J.; Tannock, I.F. Up-regulation of autophagy is a mechanism of resistance to chemotherapy and can be inhibited by pantoprazole to increase drug sensitivity. Cancer Chemother. Pharmacol. 2017, 79, 959–969. [Google Scholar] [CrossRef]
  21. Kulshrestha, A.; Katara, G.; Ibrahim, S.; Riehl, V.; Sahoo, M.; Dolan, J.; Meinke, K.; Pins, M.; Beaman, K. Targeting V-ATPase Isoform Restores Cisplatin Activity in Resistant Ovarian Cancer: Inhibition of Autophagy, Endosome Function, and ERK/MEK Pathway. J. Oncol. 2019, 2019, 1–15. [Google Scholar] [CrossRef] [Green Version]
  22. Li, Y.Y.; Lam, S.K.; Zheng, C.Y.; Ho, J.C.M. The effect of tumor microenvironment on autophagy and sensitivity to targeted therapy in EGFR-mutated lung adenocarcinoma. J. Cancer 2015, 6, 382–386. [Google Scholar] [CrossRef] [PubMed]
  23. Xiong, H.Y.; Guo, X.L.; Bu, X.X.; Zhang, S.S.; Ma, N.N.; Song, J.R.; Hu, F.; Tao, S.F.; Sun, K.; Li, R.; et al. Autophagic cell death induced by 5-FU in Bax or PUMA deficient human colon cancer cell. Cancer Lett. 2010, 288, 68–74. [Google Scholar] [CrossRef] [PubMed]
  24. Kanzawa, T.; Kondo, Y.; Ito, H.; Kondo, S.; Germano, I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 2003, 63, 2103–2108. [Google Scholar] [PubMed]
  25. Lee, Y.J.; Won, A.J.; Lee, J.; Jung, J.H.; Yoon, S.; Lee, B.M.; Kim, H.S. Molecular mechanism of SAHA on regulation of autophagic cell death in tamoxifen-resistant MCF-7 breast cancer cells. Int. J. Med. Sci. 2012, 9, 881–893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Rebecca, V.W.; Nicastri, M.C.; Fennelly, C.; Chude, C.I.; Barber-Rotenberg, J.S.; Ronghe, A.; McAfee, Q.; McLaughlin, N.P.; Zhang, G.; Goldman, A.R.; et al. PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov. 2019, 9, 220–229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Lee, S.W.; Kim, H.K.; Lee, N.H.; Yi, H.Y.; Kim, H.S.; Hong, S.H.; Hong, Y.K.; Joe, Y.A. The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells. Cancer Lett. 2015, 360, 195–204. [Google Scholar] [CrossRef]
  28. Chen, Y.; Klionsky, D.J. The regulation of autophagy—Unanswered questions. J. Cell Sci. 2011, 124, 161–170. [Google Scholar] [CrossRef] [Green Version]
  29. Wang, G.; Chen, S.; Edwards, H.; Cui, X.; Cui, L.; Ge, Y. Combination of chloroquine and GX15-070 (obatoclax) results in synergistic cytotoxicity against pancreatic cancer cells. Oncol. Rep. 2014, 32, 2789–2794. [Google Scholar] [CrossRef] [Green Version]
  30. Yin, P.; Jia, J.; Li, J.; Song, Y.; Zhang, Y.; Chen, F. ABT-737, a Bcl-2 selective inhibitor, and chloroquine synergistically kill renal cancer cells. Oncol. Res. 2016, 24, 65–72. [Google Scholar] [CrossRef]
  31. Pellegrini, P.; Strambi, A.; Zipoli, C.; Hägg-Olofsson, M.; Buoncervello, M.; Linder, S.; de Milito, A. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: Implications for cancer therapies. Autophagy 2014, 10, 562–571. [Google Scholar] [CrossRef] [Green Version]
  32. Fong, W.; To, K. Repurposing Chloroquine Analogs as an Adjuvant Cancer Therapy. Recent Pat Anticancer Drug Discov. 2021, 16, 204–221. [Google Scholar] [CrossRef] [PubMed]
  33. Hall, E.A.; Ramsey, J.E.; Peng, Z.; Hayrapetyan, D.; Shkepu, V.; O’Rourke, B.; Geiger, W.; Lam, K.; Verschraegen, C.F. Novel organometallic chloroquine derivative inhibits tumor growth. J. Cell. Biochem. 2018, 119, 5921–5933. [Google Scholar] [CrossRef] [PubMed]
  34. Baquero, P.; Dawson, A.; Mukhopadhyay, A.; Kuntz, E.M.; Mitchell, R.; Olivares, O.; Ianniciello, A.; Scott, M.T.; Dunn, K.; Nicastri, M.C.; et al. Targeting quiescent leukemic stem cells using second generation autophagy inhibitors. Leukemia 2019, 33, 981–994. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. McAfee, Q.; Zhang, Z.; Samanta, A.; Levi, S.M.; Ma, X.H.; Piao, S.; Lynch, J.P.; Uehara, T.; Sepulveda, A.R.; Davis, L.E.; et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc. Natl. Acad. Sci. USA 2012, 109, 8253–8258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Stalnecker, C.; Grover, K.; Edwards, A.; Coleman, M.; Yang, R.; DeLiberty, J.; Papke, B.; Goodwin, C.; Pierobon, M.; Petricoin, E.; et al. Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors. Cancer Res. 2022, 82, 586–598. [Google Scholar] [CrossRef]
  37. Maycotte, P.; Aryal, S.; Cummings, C.T.; Thorburn, J.; Morgan, M.J.; Thorburn, A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy 2012, 8, 200–212. [Google Scholar] [CrossRef] [Green Version]
  38. Maes, H.; Kuchnio, A.; Carmeliet, P.; Agostinis, P. Chloroquine anticancer activity is mediated by autophagy-independent effects on the tumor vasculature. Mol. Cell. Oncol. 2016, 3, e970097. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Maes, H.; Kuchnio, A.; Carmeliet, P.; Agostinis, P. How to teach an old dog new tricks: Autophagy-independent action of chloroquine on the tumor vasculature. Autophagy 2014, 10, 2082–2084. [Google Scholar] [CrossRef] [Green Version]
  40. Maes, H.; Kuchnio, A.; Peric, A.; Moens, S.; Nys, K.; DeBock, K.; Quaegebeur, A.; Schoors, S.; Georgiadou, M.; Wouters, J.; et al. Tumor vessel normalization by chloroquine independent of autophagy. Cancer Cell 2014, 26, 190–206. [Google Scholar] [CrossRef] [Green Version]
  41. Choi, D.S.; Blanco, E.; Kim, Y.; Rodriguez, A.A.; Zhao, H.; Huang, T.H.; Chen, C.; Jin, G.; Landis, M.D.; Lacey, A.; et al. Chloroquine eliminates cancer stem cells through deregulation of Jak2 and DNMT1. Stem Cells 2015, 32, 2309–2323. [Google Scholar] [CrossRef] [Green Version]
  42. White, N.J.; Watson, J.A.; Hoglund, R.M.; Chan, X.H.S.; Cheah, P.Y.; Tarning, J. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med. 2020, 17, e1003252. [Google Scholar] [CrossRef] [PubMed]
  43. Abdel-Aziz, A.K.; Saadeldin, M.K.; D’Amico, P.; Orecchioni, S.; Bertolini, F.; Curigliano, G.; Minucci, S. Preclinical models of breast cancer: Two-way shuttles for immune checkpoint inhibitors from and to patient bedside. Eur. J. Cancer 2019, 122, 22–41. [Google Scholar] [CrossRef]
  44. Hu-lieskovan, S.; Malouf, G.G.; Jacobs, I.; Chou, J.; Liu, L.; Melissa, L. Addressing resistance to immune checkpoint inhibitor therapy: An urgent unmet need. Future Oncol. 2021, 17, 1401–1439. [Google Scholar] [CrossRef]
  45. Wabitsch, S.; McVey, J.C.; Ma, C.; Ruf, B.; Kamenyeva, O.; McCallen, J.D.; Diggs, L.P.; Heinrich, B.; Greten, T.F. Hydroxychloroquine can impair tumor response to anti-PD1 in subcutaneous mouse models. iScience 2021, 24, 101990. [Google Scholar] [CrossRef] [PubMed]
  46. Morita, S.; Takahashi, T.; Yoshida, Y.; Yokota, N. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients with Cutaneous or Systemic Lupus Erythematosus. Ther. Drug Monit. 2016, 38, 259–267. [Google Scholar] [CrossRef]
  47. Carmichael, S.; Charles, B.; Tett, S. Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis. Ther. Drug Monit. 2003, 25, 671–681. [Google Scholar] [CrossRef] [PubMed]
  48. Höglund, R.; Moussavi, Y.; Ruengweerayut, R.; Cheomung, A.; Äbelö, A.; Na-Bangchang, K. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border. Malar. J. 2016, 15, 129. [Google Scholar] [CrossRef] [Green Version]
  49. Noreddin, A.; El-Khatib, W.; Aolie, J.; Salem, A.; Zhanel, G. Pharmacodynamic target attainment potential of azithromycin, clarithromycin, and telithromycin in serum and epithelial lining fluid of community-acquired pneumonia patients with penicillin-susceptible, intermediate, and resistant Streptococcus pneumoniae. Int. J. Infect. Dis. 2009, 13, 483–487. [Google Scholar] [CrossRef] [Green Version]
  50. Salem, A.; Zhanel, G.; Ibrahim, S.; Noreddin, A. Monte Carlo simulation analysis of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit-isolated methicillin-resistant Staphylococcus aureus. Clin. Exp. Pharmacol. Physiol. 2014, 41, 437–443. [Google Scholar] [CrossRef]
  51. Chatre, C.; Roubille, F.; Vernhet, H.; Jorgensen, C.; Pers, Y.M. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf. 2018, 41, 919–931. [Google Scholar] [CrossRef]
  52. Coppola, C.; Rienzo, A.; Piscopo, G.; Barbieri, A.; Arra, C.; Maurea, N. Management of QT prolongation induced by anti-cancer drugs: Target therapy and old agents. Different algorithms for different drugs. Cancer Treat. Rev. 2018, 63, 135–143. [Google Scholar] [CrossRef] [PubMed]
  53. Stokkermans, T.J.; Goyal, A.; Trichonas, G. Chloroquine And Hydroxychloroquine Toxicity. StatPearls [Internet]. Treasure Isl. StatPearls Publ. (n.d.). Available online: (accessed on 3 April 2020).
  54. Leung, L.S.B.; Neal, J.W.; Wakelee, H.A.; Sequist, L.V.; Marmor, M.F. Rapid Onset of Retinal Toxicity from High-Dose Hydroxychloroquine Given for Cancer Therapy. Am. J. Ophthalmol. 2015, 160, 799–805.e1. [Google Scholar] [CrossRef] [PubMed]
  55. Jiang, M.; Wei, Q.; Dong, G.; Komatsu, M.; Su, Y.; Dong, Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 2012, 82, 1271–1283. [Google Scholar] [CrossRef] [Green Version]
  56. Fiehn, C.; Ness, T.; Weseloh, C.; Specker, C.; Hadjiski, D.; Detert, J.; Krüger, K.; Kommission Pharmakotherapie der DGRh. Safety management of the treatment with antimalarial drugs in rheumatology. Interdisciplinary recommendations based on a systematic literature search. Z Rheumatol. 2020, 79, 186–194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Levy, M.; Buskila, D.; Gladman, D.; Urowitz, M.; Koren, G. Pregnancy outcome following first trimester exposure to chloroquine. Am. J. Perinatol. 1991, 8, 174–178. [Google Scholar] [CrossRef]
  58. Sánchez-Chapula, J.; Salinas-Stefanon, E.; Torres-Jácome, J.; Benavides-Haro, D.; Navarro-Polanco, R. Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes. J. Pharmacol. Exp. Ther. 2001, 297, 437–445. [Google Scholar]
  59. Horne, G.A.; Stobo, J.; Kelly, C.; Mukhopadhyay, A.; Latif, A.L.; Dixon-Hughes, J.; McMahon, L.; Cony-Makhoul, P.; Byrne, J.; Smith, G.; et al. A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease. Leukemia 2020, 34, 1775–1786. [Google Scholar] [CrossRef]
  60. Arnaout, A.; Robertson, S.J.; Pond, G.R.; Lee, H.; Jeong, A.; Ianni, L.; Kroeger, L.; Hilton, J.; Coupland, S.; Gottlieb, C.; et al. A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients. Breast Cancer Res. Treat. 2019, 178, 327–335. [Google Scholar] [CrossRef] [PubMed]
  61. Zeh, H.; Bahary, N.; Boone, B.A.; Singhi, A.D.; Miller-Ocuin, J.L.; Normolle, D.P.; Zureikat, A.H.; Hogg, M.E.; Bartlett, D.L.; Lee, K.K.; et al. A Randomized Phase II Preoperative Study of Autophagy Inhibition With High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients. Clin. Cancer Res. 2020, 26, 3126–3134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Barnard, R.A.; Wittenburg, L.A.; Amaravadi, R.K.; Gustafson, D.L.; Thorburn, A.; Thamm, D.H. Phase I clinical trial and pharmacodynamic evaluation of combination hydroxychloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy 2014, 10, 1415–1425. [Google Scholar] [CrossRef] [Green Version]
  63. Patel, S.; Hurez, V.; Nawrocki, S.T.; Goros, M.; Michalek, J.; Sarantopoulos, J.; Curiel, T.; Mahalingam, D. Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. Oncotarget 2016, 7, 59087–59097. [Google Scholar] [CrossRef] [Green Version]
  64. Briceño, E.; Reyes, S.; Sotelo, J. Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg. Focus 2003, 14, 2–7. [Google Scholar] [CrossRef] [PubMed]
  65. Rojas-Puentes, L.L.; Gonzalez-Pinedo, M.; Crismatt, A.; Ortega-Gomez, A.; Gamboa-Vignolle, C.; Nuñez-Gomez, R.; Dorantes-Gallareta, Y.; Arce-Salinas, C.; Arrieta, O. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiat. Oncol. 2013, 8, 209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Vogl, D.T.; Stadtmauer, E.A.; Tan, K.-S.; Heitjan, D.F.; Davis, L.E.; Pontiggia, L.; Rangwala, R.; Piao, S.; Chang, Y.C.; Scott, E.C.; et al. Combined autophagy and proteasome inhibition A phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 2014, 10, 1380–1390. [Google Scholar] [CrossRef] [Green Version]
  67. Rangwala, R.; Leone, R.; Chang, Y.C.; Fecher, L.A.; Schuchter, L.M.; Kramer, A.; Tan, K.S.; Heitjan, D.F.; Rodgers, G.; Gallagher, M.; et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 2014, 10, 1369–1379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Haas, N.B.; Appleman, L.J.; Stein, M.; Redlinger, M.; Wilks, M.; Xu, X.; Onorati, A.; Kalavacharla, A.; Kim, T.; Zhen, C.J.; et al. Autophagy inhibition to augment mTOR inhibition: A phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clin. Cancer Res. 2019, 25, 2080–2087. [Google Scholar] [CrossRef] [Green Version]
  69. Boone, B.A.; Bahary, N.; Zureikat, A.; Noser, A.J.; Normolle, D.; Wu, W.; Singhi, A.D.; Bao, P.; Lotze, M.T.; Iii, H.J.Z. Safety and Biologic Response of Pre-operative Autophagy Inhibition with Gemcitabine in Patients with Pancreatic Adenocarcinoma. Ann. Surg. Oncol. 2016, 22, 4402–4410. [Google Scholar] [CrossRef] [PubMed]
  70. Wolpin, B.M.; Rubinson, D.A.; Wang, X.; Chan, J.A.; Cleary, J.M.; Enzinger, P.C.; Fuchs, C.S.; McCleary, N.J.; Meyerhardt, J.A.; Ng, K.; et al. Phase II and Pharmacodynamic Study of Autophagy Inhibition Using Hydroxychloroquine in Patients With Metastatic Pancreatic Adenocarcinoma. Oncologist 2014, 19, 637–638. [Google Scholar] [CrossRef] [Green Version]
  71. Xu, R.; Ji, Z.; Xu, C.; Zhu, J. The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers. Medicine 2018, 97, e12912. [Google Scholar] [CrossRef]
  72. Karasic, T.B.; O’Hara, M.H.; Loaiza-Bonilla, A.; Reiss, K.A.; Teitelbaum, U.R.; Borazanci, E.; de Jesus-Acosta, A.; Redlinger, C.; Burrell, J.A.; Laheru, D.A.; et al. Effect of Gemcitabine and nab-Paclitaxel with or Without Hydroxychloroquine on Patients with Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019, 5, 993–998. [Google Scholar] [CrossRef]
  73. Fei, N.; Wen, S.; Ramanathan, R.; Hogg, M.E.; Zureikat, A.H.; Lotze, M.T.; Bahary, N.; Singhi, A.D.; Zeh, H.J.; Boone, B.A. SMAD4 loss is associated with response to neoadjuvant chemotherapy plus hydroxychloroquine in patients with pancreatic adenocarcinoma. Clin. Transl. Sci. 2021, 14, 1822–1829. [Google Scholar] [CrossRef]
  74. Samaras, P.; Tusup, M.; Nguyen-Kim, T.D.L.; Seifert, B.; Bachmann, H.; von Moos, R.; Knuth, A.; Pascolo, S. Phase I study of a chloroquine–gemcitabine combination in patients with metastatic or unresectable pancreatic cancer. Cancer Chemother. Pharmacol. 2017, 80, 1005–1012. [Google Scholar] [CrossRef]
  75. Wang, P.; Burikhanov, R.; Jayswal, R.; Weiss, H.L.; Arnold, S.M.; Villano, J.L.; Rangnekar, V.M. Neoadjuvant administration of hydroxychloroquine in a phase 1 clinical trial induced plasma par-4 levels and apoptosis in diverse tumors. Genes Cancer 2018, 9, 190–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Compter, I.; Eekers, D.B.P.; Hoeben, A.; Rouschop, K.M.A.; Reymen, B.; Ackermans, L.; Beckervordersantforth, J.; Bauer, N.J.C.; Anten, M.M.; Wesseling, P.; et al. Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: A phase IB trial. Autophagy 2021, 17, 2604–2612. [Google Scholar] [CrossRef] [PubMed]
  77. Goldberg, S.B.; Supko, J.G.; Neal, J.W.; Muzikansky, A.; Digumarthy, S.; Fidias, P.; Temel, J.S.; Heist, R.S.; Shaw, A.T.; McCarthy, P.O.; et al. A phase i study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer. J. Thorac. Oncol. 2012, 7, 1602–1608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Rosenfeld, M.R.; Ye, X.; Supko, J.G.; Desideri, S.; Grossman, S.A.; Brem, S.; Mikkelson, T.; Wang, D.; Chang, Y.C.; Hu, J.; et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 2014, 10, 1359–1368. [Google Scholar] [CrossRef]
  79. Mehnert, J.M.; Mitchell, T.C.; Huang, A.C.; Aleman, T.S.; Kim, B.J.; Schuchter, L.M.; Linette, G.P.; Karakousis, G.C.; Mitnick, S.; Giles, L.; et al. BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma. Clin. Cancer Res. 2022, 28, 1098–1106. [Google Scholar] [CrossRef]
  80. Somer, M.; Kallio, J.; Pesonen, U.; Pyykkö, K.; Huupponen, R.; Scheinin, M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br. J. Clin. Pharmacol. 2000, 49, 549–554. [Google Scholar] [CrossRef]
  81. Adedoyin, A.; Frye, R.; Mauro, K.; Branch, R. Chloroquine modulation of specific metabolizing enzymes activities: Investigation with selective five drug cocktail. Br. J. Clin. Pharmacol. 1998, 46, 215–219. [Google Scholar] [CrossRef] [Green Version]
  82. Tiberghien, F.; Loor, F. Ranking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay. Anticancer Drugs 1996, 7, 568–578. [Google Scholar] [CrossRef]
  83. Iwuagwu, M.; Aloko, K. Adsorption of paracetamol and chloroquine phosphate by some antacids. J. Pharm. Pharmacol. 1992, 44, 655–658. [Google Scholar] [CrossRef] [PubMed]
  84. Ali, H.M. Reduced ampicillin bioavailability following oral coadministration with chloroquine. J. Antimicrob. Chemother. 1985, 15, 781–784. [Google Scholar] [CrossRef]
  85. Toimela, T.; Salminen, L.; Tähti, H. Effects of tamoxifen, toremifene and chloroquine on the lysosomal enzymes in cultured retinal pigment epithelial cells. Pharmacol. Toxicol. 1998, 83, 246–251. [Google Scholar] [CrossRef] [PubMed]
  86. Nampoory, M.R.N.; Nessim, J.; Gupta, R.K.; Johny, K.V. Drug interaction of chloroquine with ciclosporin. Nephron 1992, 62, 108–109. [Google Scholar] [CrossRef] [PubMed]
  87. Seideman, P.; Albertioni, F.; Beck, O.; Eksborg, S.; Peterson, C. A Possible Mechanism of Reduced Hepatotoxicity. Arthritis Rheum. 1994, 37, 830–833. [Google Scholar] [CrossRef]
  88. Ette, E.; Brown-Awala, E.; Essien, E. Chloroquine elimination in humans: Effect of low-dose cimetidine. J. Clin. Pharmacol. 1987, 27, 813–816. [Google Scholar] [CrossRef]
  89. Adjepon-Yamoah, K.K.; Woolhouse, N.; Prescott, L. The effect of chloroquine on paracetamol disposition and kinetics. Br. J. Clin. Pharmacol. 1986, 21, 322–324. [Google Scholar] [CrossRef] [Green Version]
  90. Pukrittayakamee, S.; Tarning, J.; Jittamala, P.; Charunwatthana, P.; Lawpoolsri, S.; Lee, S.J.; Hanpithakpong, W.; Hanboonkunupakarn, B.; Day, N.P.J.; Ashley, E.A.; et al. Pharmacokinetic interactions between primaquine and chloroquine. Antimicrob. Agents Chemother. 2014, 58, 3354–3359. [Google Scholar] [CrossRef] [Green Version]
  91. McElnay, J.C.; Sidahmed, A.M.; D’Arcy, P.F.; McQuade, R.D. Chloroquine-digoxin interaction. Int. J. Pharm. 1985, 26, 267–274. [Google Scholar] [CrossRef]
  92. Shojania, K.; Koehler, B.; Elliott, T. Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis. J. Rheumatol. 1999, 26, 195–196. [Google Scholar]
  93. Hwang, S.; Mruk, K.; Rahighi, S.; Raub, A.G.; Chen, C.H.; Dorn, L.E.; Horikoshi, N.; Wakatsuki, S.; Chen, J.K.; Mochly-Rosen, D. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. Nat. Commun. 2018, 9, 4045. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Amabeoku, G.J.; Chikuni, O. Chloroquine-induced seizures in mice: The role of monoaminergic mechanisms. Eur. Neuropsychopharmacol. 1993, 3, 37–44. [Google Scholar] [CrossRef]
  95. Amabeoku, G. Involvement of GABAergic mechanisms in chloroquine-induced seizures in mice. Gen. Pharmacol. 1992, 23, 225–229. [Google Scholar] [CrossRef]
Table 1. Clinical trials of chloroquine (CQ) and hydroxychloroquine (HCQ) in cancer therapy.
Table 1. Clinical trials of chloroquine (CQ) and hydroxychloroquine (HCQ) in cancer therapy.
DrugCancer TypeTreatment Schedule of CQ or HCQ (n = Sample Size)Clinical OutcomeRef
CQGlioblastoma multiformeCQ (150 mg dose/day) was administered 24 h post-surgery and continued with radiotherapy and chemotherapy throughout the observation period (24–50 months) (n = 9/control cohort and n = 9/CQ cohort).CQ prolonged the survival compared to the controls.[64]
Glioblastoma multiformeCQ (n = 6: 200 mg, n = 3: 300 mg and n = 4: 400 mg) was started 1 week before chemoradiation (temozolomide + radiotherapy).
MTD of CQ = 200 mg.
Median survival was 11.5 and 20 months for EGFRvIII- and EGFRvIII+ patients, respectively.
Tolerability and OS supported further clinical studies.
Brain metastases from solid tumoursWhole brain irradiation (30 Gy in 10 fractions over two weeks) together with CQ (150 mg/day were administered 1 h before whole brain irradiation and continued for 4 weeks) (n = 34/placebo cohort and n = 39/CQ cohort).
CQ improved the control of brain metastasis, compared to control arm.
No differences in OS, response rate, QoL or toxicity in either arm.
Breast cancer500 mg/day as monotherapy for 2–6 weeks before surgery (n = 24/placebo cohort and n = 46/CQ cohort).
No significant effect on breast cancer proliferation (Ki67).
All AEs were grade 1, but caused ~15% to discontinue therapy.
Metastatic or unresectable pancreatic cancer3+3 dose escalation study in which patients received single weekly dose of gemcitabine followed by single weekly doses of CQ (100, 200 or 300 mg) (n = 9).
CQ addition to gemicitabine was well tolerated.
HCQPancreatic adenocarcinomaPre-operative gemcitabine + HCQ (1200 mg/kg/day) for 31 days until surgery (n = 35).
No dose-limiting toxicities and grade 4/5 treatment-related AEs.
Gemcitabine and HCQ improved the OS, compared with a previous institutional cohort.
Metastatic pancreatic
Patients received (n = 10: 400 mg or n = 10: 600 mg) HCQ BID.
At 2 months, 2 (10%) without PD.
Median PFS and OS were 46.5 and 69.0 days, respectively.
Tolerability and efficacy were similar in both dosing.
Resectable pancreatic adenocarcinomaPreoperative HCQ (600 mg BID) (n = 30/nab-paclitaxel and gemcitabine (PG) cohort and n = 34/HCQ + PG cohort).
Preoperative HCQ (600 mg BID), gemcitabine and nab-paclitaxel conferred better pathological and serum biomarker responses and was associated with autophagy inhibition and increased immune cell tumour infiltration, compared to preoperative PG.
No difference in serious AEs, OS and recurrence-free survival.
Advanced or metastatic pancreatic adenocarcinomaHCQ (600 mg BID)
(n = 57/PG cohort and n = 55/PG + HCQ cohort).
Addition of HCQ (600 mg BID) to gemcitabine and nab-paclitaxel did not improve OS at 12 months.
HCQ significantly increased the overall response rate from 21% to 38%.
Non-small cell lung cancer
Patients were randomly assigned into either HCQ (n = 8) or HCQ + erlotinib (n = 19) cohorts.
3+3 Dose escalation study in which patients initially received 400 mg/day HCQ with 200 mg increment to reach a maximum dose of 1000 mg HCQ.
Recommended Phase II dose: HCQ (1000 mg/day) + erlotinib.
28-day cycles continued until PD or unacceptable toxicity.
No dose-limiting toxicities.
Advanced solid tumours and melanomaHCQ (200–1200 mg/day) + temozolomide for 7/14 days (n = 37).
Well tolerated without recurrent dose-limiting toxicity.
MTD was not reached for HCQ.
Recommended Phase II dose: HCQ (600 mg BID)+ temozolomide.
PR [3/22 (14%)] in metastatic melanoma patients.
Glioblastoma multiformePhase I: HCQ (200 to 800 mg/day) with radiotherapy and temozolomide (n = 16).
Phase II: HCQ (200 to 800 mg/day) with radiotherapy and temozolomide (n = 76).
HCQ (MTD = 600 mg/day) with radiotherapy + temozolomide was associated with inconsistent autophagy inhibition and no improvement in OS.
Advanced metastatic colorectal cancerHCQ (600 mg/day) + vorinostat in a 3-week cycle (n = 20).
40% had Grade 3/4 treatment-related AEs: fatigue, nausea, vomiting, and anaemia.
The combination was associated with boosted anti-tumour immunity and autophagy inhibition.
Refractory/ relapsed myelomaTwo week run-in of HCQ as a monotherapy (100, 200, 400, 800 or 1200 mg/day) followed by combination therapy with bortezomib (n = 25).
Recommended Phase 2 dose: HCQ (600 mg BID) for 56 days + bortezomib.
Dose-related GIT toxicity and cytopenias were noticed.
Of 22 patients, 3 (14%) had very good PR.
Renal cell carcinomaEverolimus + HCQ (400 or 600 mg BID) (n = 38).
First Cycle (35 days): 1-week everolimus alone.
Subsequent cycles (28 days/cycle): everolimus +HCQ.
No dose-limiting toxicity in Phase I.
Recommended Phase II dose: HCQ (600 mg BID) + everolimus.
Early-stage solid tumors200 or 400 mg BID for 14 days before surgery (n = 9).
Well-tolerated with no dose limiting toxicities or serious AEs.
Tumors from the eight HCQ-treated patients with high plasma Par-4 levels underwent apoptosis.
P62/sequestsome-1 was induced in tumors of all nine HCQ-treated patients.
Chronic phase chronic myeloid leukemiaImatinib (n = 30) or imatinib + HCQ (400 mg BID) (n = 32) for 12 months.Imatinib + HCQ was tolerated with modest improvement in BCR-ABL1 qPCR levels at 12 and 24 months.[59]
BRAFV600-mutant melanoma
Patients (n = 38) were treated with dabrafenib and trametinib for one week and then HCQ (starting Phase I dose = 400 mg BID) was co-administered. Treatment continued until PD, and after PD in the case of isolated progression, which could be locally treated.
The combination regimen was tolerable.
PFS did not meet the prespecified threshold, but tended to be promising in patients with elevated LDH and prior treatment.
Randomized study has been launched.
AEs: adverse events, CQ: chloroquine, HCQ: hydroxychloroquine, MTD: maximum tolerated dose, OS: overall survival, PD; progressive disease, PG: nab-paclitaxel and gemcitabine, PR: partial response, SD: stable disease, QoL: quality of life.
Table 2. Known and potential drug–drug interactions of chloroquine (CQ) and hydroxychloroquine (HCQ).
Table 2. Known and potential drug–drug interactions of chloroquine (CQ) and hydroxychloroquine (HCQ).
DrugInteracting DrugType of Interaction/RecommendationsRef
CQSome antacidsSome antacids decreases CQ bioavailability and time spacing >4 h is recommended.[83]
CQAmpicillinCQ decreases the bioavailability of ampicillin [84]
CQ/HCQQT Prolongation inducing drugsCo-administration of >1 QT prolonging drugs can increase the risk of developing prolonged QT associated-arrthymia.[51,52,58]
CQ/HCQTamoxifenIncreased risk for retinopathy.[56,85]
CQCiclosporin(cyclosporin)Three-day CQ administration was associated with elevated serum ciclosporin and creatinine levels which was reversed one week after CQ discontinuation.[86]
CQMethotrexateCQ decreases the area plasma under the curve of methotrexate. [87]
CQCimetidineCimetidine impairs CQ elimination.[88]
CQAcetaminophen (Paracetamol)CQ increases the peak plasma levels and AUC of paracetamol.[89]
CQPrimaquineCQ increases the plasma levels of primaquine and carboxyprimaquine and its use is associated with slight corrected QT (QTc) interval prolongation.[90]
CQDigoxinCQ increases the serum levels of digoxin which warrants careful monitoring.[91]
CQCisplatinCQ exacerbates acute cisplatin-induced nephrotoxicity.[55]
HCQInsulin and hypoglycaemic drugsHCQ induces hypoglycaemia and dose re-adjustment of insulin or hypoglycaemic drugs is necessary.[92]
HCQMetoprololHCQ increases the bioavailability of metoprolol.[80]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Abdel-Aziz, A.K.; Saadeldin, M.K.; Salem, A.H.; Ibrahim, S.A.; Shouman, S.; Abdel-Naim, A.B.; Orecchia, R. A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer. Future Pharmacol. 2022, 2, 431-443.

AMA Style

Abdel-Aziz AK, Saadeldin MK, Salem AH, Ibrahim SA, Shouman S, Abdel-Naim AB, Orecchia R. A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer. Future Pharmacology. 2022; 2(4):431-443.

Chicago/Turabian Style

Abdel-Aziz, Amal Kamal, Mona Kamal Saadeldin, Ahmed Hamed Salem, Safaa A. Ibrahim, Samia Shouman, Ashraf B. Abdel-Naim, and Roberto Orecchia. 2022. "A Critical Review of Chloroquine and Hydroxychloroquine as Potential Adjuvant Agents for Treating People with Cancer" Future Pharmacology 2, no. 4: 431-443.

Article Metrics

Back to TopTop