Artículos de revistas
Chloroquine: Modes Of Action Of An Undervalued Drug
Registro en:
Immunology Letters. , v. 153, n. 1/Fev, p. 50 - 57, 2013.
10.1016/j.imlet.2013.07.004
2-s2.0-84882703929
Autor
Thome R.
Lopes S.C.P.
Costa F.T.M.
Verinaud L.
Institución
Resumen
For more than two decades, chloroquine (CQ) was largely and deliberately used as first choice drug for malaria treatment. However, worldwide increasing cases of resistant strains of Plasmodium have hampered its use. Nevertheless, CQ has recently been tested as adjunct therapy in several inflammatory situations, such as rheumatoid arthritis and transplantation procedures, presenting intriguing and promising results. In this review, we discuss recent findings and CQ mechanisms of action vis-à-vis its use as a broad adjunct therapy. © 2013 Elsevier B.V. 153 1/Fev 50 57 (2011) World Malaria Report 2011, , World Health Organization, Geneva World Health Organization A research agenda for malaria eradication: drugs (2011) PLoS Medicine, 8, pp. e1000402. , malERA Consultative Group on Drugs Plowe, C.V., The evolution of drug-resistant malaria (2009) Transactions of the Royal Society of Tropical Medicine and Hygiene, 103 (SUPPL. 1), pp. S11-S14 Summers, R.L., Nash, M.N., Martin, R.E., Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics (2012) Cellular and Molecular Life Sciences, 69, pp. 1967-1995 A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA Study (1995) American Journal of Medicine, 98, pp. 156-168 Bezerra, E.L., Vilar, M.J., da Trindade Neto, P.B., Sato, E.L., Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus (2005) Arthritis and Rheumatism, 52, pp. 3073-3078 Ben-Zvi, I., Kivity, S., Langevitz, P., Shoenfeld, Y., Hydroxychloroquine: from malaria to autoimmunity (2012) Clinical Reviews in Allergy & Immunology, 42, pp. 145-153 Homewood, C.A., Warhurst, D.C., Peters, W., Baggaley, V.C., Lysosomes, pH and the anti-malarial action of chloroquine (1972) Nature, 235, pp. 50-52 Chiang, G., Sassaroli, M., Louie, M., Chen, H., Stecher, V.J., Sperber, K., Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine (1996) Clinical Therapeutics, 18, pp. 1080-1092 Sperber, K., Chiang, G., Chen, H., Ross, W., Chusid, E., Gonchar, M., Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with human immunodeficiency virus type 1 (1997) Clinical Therapeutics, 19, pp. 913-923 Bernstein, H.N., Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy (1983) American Journal of Medicine, 75, pp. 25-34 Karres, I., Chloroquine inhibits proinflammatory cytokine release into human whole blood (1998) American Journal of Physiology, 274, pp. R1058-R1064 Ertel, W., Morrison, M.H., Ayala, A., Chaudry, I.H., Chloroquine attenuates hemorrhagic shock-induced immunosuppression and decreases susceptibility to sepsis (1992) Archives of Surgery, 127, pp. 70-75. , [discussion 75-76] Loehberg, C.R., Strissel, P.L., Dittrich, R., Strick, R., Dittmer, J., Dittmer, A., Akt and p53 are potential mediators of reduced mammary tumor growth by Chloroquine and the mTOR inhibitor RAD001 (2012) Biochemical Pharmacology, 83, pp. 480-488 Sperber, K., Kalb, T.H., Stecher, V.J., Banerjee, R., Mayer, L., Inhibition of human immunodeficiency virus type 1 replication by hydroxychloroquine in T cells and monocytes (1993) AIDS Research and Human Retroviruses, 9, pp. 91-98 Yoshimura, A., Kuroda, K., Kawasaki, K., Yamashina, S., Maeda, T., Ohnishi, S., Infectious cell entry mechanism of influenza virus (1982) Journal of Virology, 43, pp. 284-293 Shibata, M., Aoki, H., Tsurumi, T., Sugiura, Y., Nishiyama, Y., Suzuki, S., Mechanism of uncoating of influenza B virus in MDCK cells: action of chloroquine (1983) Journal of General Virology, 64, pp. 1149-1156 Ooi, E.E., Chew, J.S., Loh, J.P., Chua, R.C., In vitro inhibition of human influenza A virus replication by chloroquine (2006) Virology Journal, 3, p. 39 Di Trani, L., Savarino, A., Campitelli, L., Norelli, S., Puzelli, S., D'Ostilio, D., Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses (2007) Virology Journal, 4, p. 39 Misinzo, G., Delputte, P.L., Nauwynck, H.J., Inhibition of endosome-lysosome system acidification enhances porcine circovirus 2 infection of porcine epithelial cells (2008) Journal of Virology, 82, pp. 1128-1135 Savarino, A., A historical sketch of the discovery and development of HIV-1 integrase inhibitors (2006) Expert Opinion on Investigational Drugs, 15, pp. 1507-1522 Bernstein, H.N., Chloroquine ocular toxicity (1967) Survey of Ophthalmology, 12, pp. 415-447 Sperber, K., Louie, M., Kraus, T., Proner, J., Sapira, E., Lin, S., Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1 (1995) Clinical Therapeutics, 17, pp. 622-636 Murray, S.M., Down, C.M., Boulware, D.R., Stauffer, W.M., Cavert, W.P., Schacker, T.W., Reduction of immune activation with chloroquine therapy during chronic HIV infection (2010) Journal of Virology, 84, pp. 12082-12086 Piconi, S., Parisotto, S., Rizzardini, G., Passerini, S., Terzi, R., Argenteri, B., Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders (2011) Blood, 118, pp. 3263-3272 Soumelis, V., Scott, I., Gheyas, F., Bouhour, D., Cozon, G., Cotte, L., Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients (2001) Blood, 98, pp. 906-912 Martinson, J.A., Montoya, C.J., Usuga, X., Ronquillo, R., Landay, A.L., Desai, S.N., Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation (2010) Antimicrobial Agents and Chemotherapy, 54, pp. 871-881 Jiang, M.C., Lin, J.K., Chen, S.S., Inhibition of HIV-1 Tat-mediated transactivation by quinacrine and chloroquine (1996) Biochemical and Biophysical Research Communications, 226, pp. 1-7 Fredericksen, B.L., Wei, B.L., Yao, J., Luo, T., Garcia, J.V., Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus (2002) Journal of Virology, 76, pp. 11440-11446 Canadian Consensus Conference on hydroxychloroquine (2000) Journal of Rheumatology, 27, pp. 2919-2921. , Canadian Rheumatology Association Gladman, D.D., Urowitz, M.B., Senecal, J.L., Fortin, P.J., Petty, R.E., Esdaile, J.M., Aspects of use of antimalarials in systemic lupus erythematosus (1998) Journal of Rheumatology, 25, pp. 983-985 Rahman, A., Isenberg, D.A., Systemic lupus erythematosus (2008) New England Journal of Medicine, 358, pp. 929-939 Slater, A.F., Chloroquine: mechanism of drug action and resistance in Plasmodium falciparum (1993) Pharmacology & Therapeutics, 57, pp. 203-235 Tan, E.M., Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology (1989) Advances in Immunology, 44, pp. 93-151 Casciola-Rosen, L.A., Anhalt, G., Rosen, A., Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes (1994) Journal of Experimental Medicine, 179, pp. 1317-1330 A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group (1991) N Engl J Med, 324, pp. 150-154 Fessler, B.J., Systemic lupus erythematosus in three ethnic groups: XVI. Association of hydroxychloroquine use with reduced risk of damage accrual (2005) Arthritis and Rheumatism, 52, pp. 1473-1480 Alarcon, G.S., Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINAL) (2007) Annals of the Rheumatic Diseases, 66, pp. 1168-1172 Ruiz-Irastorza, G., Effect of antimalarials on thrombosis and survival in patients with systemic lupus erythematosus (2006) Lupus, 15, pp. 577-583 Tam, L.S., Gladman, D.D., Hallett, D.C., Rahman, P., Urowitz, M.B., Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus (2000) Journal of Rheumatology, 27, pp. 2142-2145 Levy, R.A., Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study (2001) Lupus, 10, pp. 401-404 Lesiak, A., Narbutt, J., Kobos, J., Kordek, R., Sysa-Jedrzejowska, A., Norval, M., Systematic administration of chloroquine in discoid lupus erythematosus reduces skin lesions via inhibition of angiogenesis (2009) Clinical and Experimental Dermatology, 34, pp. 570-575 Kreuter, A., Gaifullina, R., Tigges, C., Kirschke, J., Altmeyer, P., Gambichler, T., Lupus erythematosus tumidus: response to antimalarial treatment in 36 patients with emphasis on smoking (2009) Archives of Dermatology, 145, pp. 244-248 Coatney, G.R., Pitfalls in a discovery: the chronicle of chloroquine (1963) American Journal of Tropical Medicine and Hygiene, 12, pp. 121-128 Ikeda, T., Kanazawa, N., Furukawa, F., Hydroxychloroquine administration for Japanese lupus erythematosus in Wakayama: a pilot study (2012) Journal of Dermatology, 39, pp. 531-535 Kuhn, A., Ruland, V., Bonsmann, G., Cutaneous lupus erythematosus: update of therapeutic options. Part I (2011) Journal of the American Academy of Dermatology, 65, pp. e179-e193 Momose, Y., Arai, S., Eto, H., Kishimoto, M., Okada, M., Experience with the use of hydroxychloroquine for the treatment of lupus erythematosus (2013) Journal of Dermatology, 40, pp. 94-97 Arnett, F.C., Edworthy, S.M., Bloch, D.A., McShane, D.J., Fries, J.F., Cooper, N.S., The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis (1988) Arthritis and Rheumatism, 31, pp. 315-324 Louzada-Junior, P., Freitas, M.V., Oliveira, R.D., Deghaide, N.H., Conde, R.A., Bertolo, M.B., A majority of Brazilian patients with rheumatoid arthritis HLA-DRB1 alleles carry both the HLA-DRB1 shared epitope and anti-citrunillated peptide antibodies (2008) Brazilian Journal of Medical and Biological Research, 41, pp. 493-499 Perricone, C., Ceccarelli, F., Valesini, G., An overview on the genetic of rheumatoid arthritis: a never-ending story (2011) Autoimmunity Reviews, 10, pp. 599-608 Takayanagi, H., Inflammatory bone destruction and osteoimmunology (2005) Journal of Periodontal Research, 40, pp. 287-293 Takayanagi, H., Oda, H., Yamamoto, S., Kawaguchi, H., Tanaka, S., Nishikawa, T., A new mechanism of bone destruction in rheumatoid arthritis: synovial fibroblasts induce osteoclastogenesis (1997) Biochemical and Biophysical Research Communications, 240, pp. 279-286 Yamada, H., Nakashima, Y., Okazaki, K., Mawatari, T., Fukushi, J.I., Kaibara, N., Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis (2008) Annals of the Rheumatic Diseases, 67, pp. 1299-1304 Hashimoto, M., Hirota, K., Yoshitomi, H., Maeda, S., Teradaira, S., Akizuki, S., Complement drives Th17 cell differentiation and triggers autoimmune arthritis (2009) Journal of Experimental Medicine, 207, pp. 1135-1143 Loeb, R.F., Clark, W.M., Coatney, G.R., Coggeshall, T., Dieuaide, F.R., Dochez, A.R., Activity of a new antimalarial agent, chloroquine (SN 7618) (1946) Journal of the American Medical Association, 130, p. 1069 Korn, T., Bettelli, E., Oukka, M., Kuchroo, V.K., IL-17 and Th17 Cells (2009) Annual Review of Immunology, 27, pp. 485-517 Felson, D.T., Anderson, J.J., Meenan, R.F., The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses (1990) Arthritis and Rheumatism, 33, pp. 1449-1461 Scott, D.L., Dawes, P.T., Tunn, E., Fowler, P.D., Shadforth, M.F., Fisher, J., Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study (1989) British Journal of Rheumatology, 28, pp. 128-133 McCarty, D.J., Carrera, G.F., Intractable rheumatoid arthritis. Treatment with combined cyclophosphamide, azathioprine, and hydroxychloroquine (1982) JAMA: Journal of the American Medical Association, 248, pp. 1718-1723 Bunch, T.W., O'Duffy, J.D., Tompkins, R.B., O'Fallon, W.M., Controlled trial of hydroxychloroquine and D-penicillamine singly and in combination in the treatment of rheumatoid arthritis (1984) Arthritis and Rheumatism, 27, pp. 267-276 Gibson, T., Emery, P., Armstrong, R.D., Crisp, A.J., Combined, P.G.S., D-penicillamine and chloroquine treatment of rheumatoid arthritis - a comparative study (1987) British Journal of Rheumatology, 26, pp. 279-284 Thome, R., Moraes, A.S., Bombeiro, A.L., Farias, A.D., Francelin, C., da Costa, T.A., Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis (2013) PLoS ONE, 8, pp. e65913 Schultz, K.R., Gilman, A.L., The lysosomotropic amines, chloroquine and hydroxychloroquine: a potentially novel therapy for graft-versus-host disease (1997) Leukemia & Lymphoma, 24, pp. 201-210 Schultz, K.R., Su, W.N., Hsiao, C.C., Doho, G., Jevon, G., Bader, S., Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production (2002) Biology of Blood and Marrow Transplantation, 8, pp. 648-655 Gilman, A.L., Beams, F., Tefft, M., Mazumder, A., The effect of hydroxychloroquine on alloreactivity and its potential use for graft-versus-host disease (1996) Bone Marrow Transplantation, 17, pp. 1069-1075 Harinasuta, T., Suntharasamai, P., Viravan, C., Chloroquine-resistant falciparum malaria in Thailand (1965) Lancet, 2, pp. 657-660 Gilman, A.L., Chan, K.W., Mogul, A., Morris, C., Goldman, F.D., Boyer, M., Hydroxychloroquine for the treatment of chronic graft-versus-host disease (2000) Biology of Blood and Marrow Transplantation, 6, pp. 327-334 Schultz, K.R., Bader, S., Paquet, J., Li, W., Chloroquine treatment affects T-cell priming to minor histocompatibility antigens and graft-versus-host disease (1995) Blood, 86, pp. 4344-4352 Hobbs, H.E., Sorsby, A., Freedman, A., Retinopathy following chloroquine therapy (1959) Lancet, 2, pp. 478-480 Madalena, B.V., Oshima, A., Serracarbassa, P.D., Amsler grid and visual field on screening for chloroquine retinopathy (2012) Arquivos brasileiros de oftalmologia, 75, pp. 170-173 Levy, G.D., Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice (1997) Arthritis and Rheumatism, 40, pp. 1482-1486 Marmor, M.F., Kellner, U., Lai, T.Y., Lyons, J.S., Meiler, W.F., Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2011) Ophthalmology, 118, pp. 415-422 Marmor, M.F., Carr, R.E., Easterbrook, M., Farjo, A.A., Mieler, W.F., Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology (2002) Ophthalmology, 109, pp. 1377-1382 Rossi, P., Fossaluzza, V., Gonano, L., Localized scleroderma evolving into systemic sclerosis (1985) Journal of Rheumatology, 12, pp. 629-630 Raines, M.F., Bhargava, S.K., Rosen, E.S., The blood-retinal barrier in ch Sidhu, A.B., Verdier-Pinard, D., Fidock, D.A., Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations (2002) Science, 298, pp. 210-213 Kublin, J.G., Cortese, J.F., Njunju, E.M., Mukadam, R.A., Wirima, J.J., Kazembe, P.N., Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi (2003) Journal of Infectious Diseases, 187, pp. 1870-1875 Mita, T., Kaneko, A., Lum, J.K., Bwijo, B., Takechi, M., Zungu, I.L., Recovery of chloroquine sensitivity and low prevalence of the Plasmodium falciparum chloroquine resistance transporter gene mutation K76T following the discontinuance of chloroquine use in Malawi (2003) American Journal of Tropical Medicine and Hygiene, 68, pp. 413-415 Mwai, L., Ochong, E., Abdirahman, A., Kiara, S.M., Ward, S., Kokwaro, G., Chloroquine resistance before and after its withdrawal in Kenya (2009) Malaria Journal, 8, p. 106 Laufer, M.K., Thesing, P.C., Eddington, N.D., Masonga, R., Dzinjalamala, F.K., Takala, S.L., Return of chloroquine antimalarial efficacy in Malawi (2006) The New England Journal of Medicine, 355, pp. 1959-1966 Ndiaye, M., Faye, B., Tine, R., Ndiaye, J.L., Lo, A., Abiola, A., Assessment of the molecular marker of Plasmodium falciparum chloroquine resistance (Pfcrt) in Senegal after several years of chloroquine withdrawal (2012) American Journal of Tropical Medicine and Hygiene, 87, pp. 640-645 Wurtz, N., Fall, B., Pascual, A., Diawara, S., Sow, K., Baret, E., Prevalence of molecular markers of Plasmodium falciparum drug resistance in Dakar, Senegal (2012) Malaria Journal, 11, p. 197 Gharbi, M., Flegg, J.A., Hubert, V., Kendjo, E., Metcalf, J.E., Bertaux, L., Longitudinal study assessing the return of chloroquine susceptibility of Plasmodium falciparum in isolates from travellers returning from West and Central Africa, 2000-2011 (2013) Malaria Journal, 12, p. 35 Baird, J.K., Resistance to therapies for infection by Plasmodium vivax (2009) Clinical Microbiology Reviews, 22, pp. 508-534 Rieckmann, K.H., Davis, D.R., Hutton, D.C., Plasmodium vivax resistance to chloroquine (1989) Lancet, 2, pp. 1183-1184 Castillo, C.M., Osorio, L.E., Palma, G.I., Assessment of therapeutic response of Plasmodium vivax and Plasmodium falciparum to chloroquine in a Malaria transmission free area in Colombia (2002) Memorias do Instituto Oswaldo Cruz, 97, pp. 559-562 Ruebush, T.K., Zegarra, J., Cairo, J., Andersen, E.M., Green, M., Pillai, D.R., Chloroquine-resistant Plasmodium vivax malaria in Peru (2003) American Journal of Tropical Medicine and Hygiene, 69, pp. 548-552 Soto, J., Toledo, J., Gutierrez, P., Luzz, M., Llinas, N., Cedeno, N., Plasmodium vivax clinically resistant to chloroquine in Colombia (2001) American Journal of Tropical Medicine and Hygiene, 65, pp. 90-93 Sumawinata, I.W., Bernadeta Leksana, B., Sutamihardja, A., Purnomo Subianto, B., Very high risk of therapeutic failure with chloroquine for uncomplicated Plasmodium falciparum and P. vivax malaria in Indonesian Papua (2003) American Journal of Tropical Medicine and Hygiene, 68, pp. 416-420 Ratcliff, A., Siswantoro, H., Kenangalem, E., Wuwung, M., Brockman, A., Edstein, M.D., Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia (2007) Transactions of the Royal Society of Tropical Medicine and Hygiene, 101, pp. 351-359 Tjitra, E., Anstey, N.M., Sugiarto, P., Warikar, N., Kenangalem, E., Karyana, M., Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia (2008) PLoS Medicine, 5, pp. e128 Bray, P.G., Hawley, S.R., Mungthin, M., Ward, S.A., Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum (1996) Molecular Pharmacology, 50, pp. 1559-1566 Slater, A.F., Swiggard, W.J., Orton, B.R., Flitter, W.D., Goldberg, D.E., Cerami, A., An iron-carboxylate bond links the heme units of malaria pigment (1991) Proceedings of the National Academy of Sciences of the United States of America, 88, pp. 325-329 Bray, P.G., Janneh, O., Raynes, K.J., Mungthin, M., Ginsburg, H., Ward, S.A., Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum (1999) Journal of Cell Biology, 145, pp. 363-376 Bray, P.G., Mungthin, M., Ridley, R.G., Ward, S.A., Access to hematin: the basis of chloroquine resistance (1998) Molecular Pharmacology, 54, pp. 170-179 Pagola, S., Stephens, P.W., Bohle, D.S., Kosar, A.D., Madsen, S.K., The structure of malaria pigment beta-haematin (2000) Nature, 404, pp. 307-310 Sullivan, D.J., Gluzman, I.Y., Russell, D.G., Goldberg, D.E., On the molecular mechanism of chloroquine's antimalarial action (1996) Proceedings of the National Academy of Sciences of the United States of America, 93, pp. 11865-11870 Sullivan, D.J., Matile, H., Ridley, R.G., Goldberg, D.E., A common mechanism for blockade of heme polymerization by antimalarial quinolines (1998) Journal of Biological Chemistry, 273, pp. 31103-31107 Fitch, C.D., Chevli, R., Banyal, H.S., Phillips, G., Pfaller, M.A., Krogstad, D.J., Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex (1982) Antimicrobial Agents and Chemotherapy, 21, pp. 819-822 Krogstad, D.J., Schlesinger, P.H., A perspective on antimalarial action: effects of weak bases on Plasmodium falciparum (1986) Biochemical Pharmacology, 35, pp. 547-552 Krogstad, D.J., Schlesinger, P.H., Gluzman, I.Y., Antimalarials increase vesicle pH in Plasmodium falciparum (1985) Journal of Cell Biology, 101, pp. 2302-2309 Wunsch, S., Sanchez, C.P., Gekle, M., Grosse-Wortmann, L., Wiesner, J., Lanzer, M., Differential stimulation of the Na+/H+ exchanger determines chloroquine uptake in Plasmodium falciparum (1998) Journal of Cell Biology, 140, pp. 335-345 Sanchez, C.P., Wunsch, S., Lanzer, M., Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype (1997) Journal of Biological Chemistry, 272, pp. 2652-2658 Fitch, C.D., Chloroquine resistance in malaria: a deficiency of chloroquine binding (1969) Proceedings of the National Academy of Sciences of the United States of America, 64, pp. 1181-1187 Krogstad, D.J., Gluzman, I.Y., Kyle, D.E., Oduola, A.M., Martin, S.K., Milhous, W.K., Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance (1987) Science, 238, pp. 1283-1285 Fidock, D.A., Nomura, T., Talley, A.K., Cooper, R.A., Dzekunov, S.M., Ferdig, M.T., Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance (2000) Molecular Cell, 6, pp. 861-871 Kuhn, Y., Sanchez, C.P., Ayoub, D., Saridaki, T., van Dorsselaer, A., Lanzer, M., Trafficking of the phosphoprotein PfCRT to the digestive vacuolar membrane in Plasmodium falciparum (2010) Traffic, 11, pp. 236-249 Lakshmanan, V., Bray, P.G., Verdier-Pinard, D., Johnson, D.J., Horrocks, P., Muhle, R.A., A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance (2005) EMBO Journal, 24, pp. 2294-2305 Martin, R.E., Marchetti, R.V., Cowan, A.I., Howitt, S.M., Broer, S., Kirk, K., Chloroquine transport via the malaria parasite's chloroquine resistance transporter (2009) Science, 325, pp. 1680-1682 Peel, S.A., The ABC transporter genes of Plasmodium falciparum and drug resistance (2001) Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy, 4, pp. 66-74 Duraisingh, M.T., Cowman, A.F., Contribution of the pfmdr1 gene to antimalarial drug-resistance (2005) Acta Tropica, 94, pp. 181-190 Djimde, A., Doumbo, O.K., Cortese, J.F., Kayentao, K., Doumbo, S., Diourte, Y., A molecular marker for chloroquine-resistant falciparum malaria (2001) New England Journal of Medicine, 344, pp. 257-263 Babiker, H.A., Pringle, S.J., Abdel-Muhsin, A., Mackinnon, M., Hunt, P., Walliker, D., High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance Gene pfmdr1 (2001) Journal of Infectious Diseases, 183, pp. 1535-1538 Adagu, I.S., Warhurst, D.C., Plasmodium falciparum: linkage disequilibrium between loci in chromosomes 7 and 5 and chloroquine selective pressure in Northern Nigeria (2001) Parasitology, 123, pp. 219-224 Mu, J., Ferdig, M.T., Feng, X., Joy, D.A., Duan, J., Furuya, T., Multiple transporters associated with malaria parasite responses to chloroquine and quinine (2003) Molecular Microbiology, 49, pp. 977-989 Ngo, T., Duraisingh, M., Reed, M., Hipgrave, D., Biggs, B., Cowman, A.F., Analysis of pfcrt, pfmdr1, dhfr, and dhps mutations and drug sensitivities in Plasmodium falciparum isolates from patients in Vietnam before and after treatment with artemisinin (2003) American Journal of Tropical Medicine and Hygiene, 68, pp. 350-356 Wellems, T.E., Plowe, C.V., Chloroquine-resistant malaria (2001) Journal of Infectious Diseases, 184, pp. 770-776 (2010) Global Report on Antimalarial Drug Efficacy and Drug Resistance: 2000-2010, , World Health Organization, Geneva World Health Organization Martin, S.K., Oduola, A.M., Milhous, W.K., Reversal of chloroquine resistance in Plasmodium falciparum by verapamil (1987) Science, 235, pp. 899-901 Egan, T.J., Kaschula, C.H., Strategies to reverse drug resistance in malaria (2007) Current Opinion in Infectious Diseases, 20, pp. 598-604 Guantai, E., Chibale, K., Chloroquine resistance: proposed mechanisms and countermeasures (2010) Current Drug Delivery, 7, pp. 312-323 Martin, R.E., Butterworth, A.S., Gardiner, D.L., Kirk, K., McCarthy, J.S., Skinner-Adams, T.S., Saquinavir inhibits the malaria parasite's chloroquine resistance transporter (2012) Antimicrobial Agents and Chemotherapy, 56, pp. 2283-2289 De, D., Krogstad, F.M., Cogswell, F.B., Krogstad, D.J., Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro (1996) American Journal of Tropical Medicine and Hygiene, 55, pp. 579-583 Ridley, R.G., Hofheinz, W., Matile, H., Jaquet, C., Dorn, A., Masciadri, R., 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum (1996) Antimicrobial Agents and Chemotherapy, 40, pp. 1846-1854 Biot, C., Glorian, G., Maciejewski, L.A., Synthesis, B.J.S., Antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue (1997) Journal of Medicinal Chemistry, 40, pp. 3715-3718 Sundelin, S.P., Terman, A., Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells (2002) APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica, 110, pp. 481-489 de Duve, C., de Barsy, T., Poole, B., Trouet, A., Tulkens, P., Van Hoof, F., Commentary. Lysosomotropic agents (1974) Biochemical Pharmacology, 23, pp. 2495-2531 Fox, R.I., Mechanism of action of hydroxychloroquine as an antirheumatic drug (1993) Seminars in Arthritis and Rheumatism, 23, pp. 82-91 Mares, V., Schultze, B., Maurer, W., Stability of DNA in Purkinje cell nuclei of the mouse. An autoradiographic study (1974) Journal of Cell Biology, 63, pp. 665-674 McChesney, E.W., Banks, W.F., Sullivan, D.J., Metabolism of chloroquine and hydroxychloroquine in albino and pigmented rats (1965) Toxicology and Applied Pharmacology, 7, pp. 627-636 Wibo, M., Poole, B., Protein degradation in cultured cells. II. The uptake of chloroquine by rat fibroblasts and the inhibition of cellular protein degradation and cathepsin B1 (1974) Journal of Cell Biology, 63, pp. 430-440 Leung, K.K., Shilton, B.H., Chloroquine binding reveals flavin redox switch function of quinone reductase 2 (2013) Journal of Biological Chemistry, 288, pp. 11242-11251 Gong, X., Kole, L., Iskander, K., Jaiswal, A.K., NRH:quinone oxidoreductase 2 and NAD(P)H:quinone oxidoreductase 1 protect tumor suppressor p53 against 20s proteasomal degradation leading to stabilization and activation of p53 (2007) Cancer Research, 67, pp. 5380-5388 Kwiek, J.J., Haystead, T.A., Rudolph, J., Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines (2004) Biochemistry, 43, pp. 4538-4547 Long, D.J., Iskander, K., Gaikwad, A., Arin, M., Roop, D.R., Knox, R., Disruption of dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2) leads to myeloid hyperplasia of bone marrow and decreased sensitivity to menadione toxicity (2002) Journal of Biological Chemistry, 277, pp. 46131-46139 Ahn, K.S., Gong, X., Sethi, G., Chaturvedi, M.M., Jaiswal, A.K., Aggarwal, B.B., Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases (2007) Cancer Research, 67, pp. 10004-10011 Savarino, A., Boelaert, J.R., Cassone, A., Majori, G., Cauda, R., Effects of chloroquine on viral infections: an old drug against today's diseases (2003) Lancet Infectious Diseases, 3, pp. 722-727 Bergmann, M., Schutt, F., Holz, F.G., Kopitz, J., Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration (2004) FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 18, pp. 562-564 Garulli, B., Stillitano, M.G., Barnaba, V., Castrucci, M.R., Primary CD8+ T-cell response to soluble ovalbumin is improved by chloroquine treatment in vivo (2008) Clinical and Vaccine Immunology: CVI, 15, pp. 1497-1504 Li, Z., Jansen, M., Pierre, S.R., Figueiredo-Pereira, M.E., Neurodegeneration: linking ubiquitin/proteasome pathway impairment with inflammation (2003) The International Journal of Biochemistry & Cell Biology, 35, pp. 547-552 Gottlieb, R.A., Nordberg, J., Skowronski, E., Babior, B.M., Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification (1996) Proceedings of the National Academy of Sciences of the United States of America, 93, pp. 654-658 Yoon, Y.H., Cho, K.S., Hwang, J.J., Lee, S.J., Choi, J.A., Koh, J.Y., Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells (2010) Investigative Ophthalmology & Visual Science, 51, pp. 6030-6037 Rubinsztein, D.C., Gestwicki, J.E., Murphy, L.O., Klionsky, D.J., Potential therapeutic applications of autophagy (2007) Nature Reviews Drug Discovery, 6, pp. 304-312 Orvedahl, A., Levine, B., Eating the enemy within: autophagy in infectious diseases (2009) Cell Death and Differentiation, 16, pp. 57-69 Chiu, H.C., Kulp, S.K., Soni, S., Wang, D., Gunn, J.S., Schlesinger, L.S., Eradication of intracellular Salmonella enterica serovar Typhimurium with a small-molecule, host cell-directed agent (2009) Antimicrobial Agents and Chemotherapy, 53, pp. 5236-5244 Amaravadi, R.K., Lippincott-Schwartz, J., Yin, X.M., Weiss, W.A., Takebe, N., Timmer, W., Principles and current strategies for targeting autophagy for cancer treatment (2011) Clinical Cancer Research, 17, pp. 654-666 Demachi-Okamura, A., Torikai, H., Akatsuka, Y., Miyoshi, H., Yoshimori, T., Kuzushima, K., Autophagy creates a CTL epitope that mimics tumor-associated antigens (2012) PLoS ONE, 7, pp. e47126 Williams, M.A., Bevan, M.J., Effector and memory CTL differentiation (2007) Annual Review of Immunology, 25, pp. 171-192 Kalia, S., Dutz, J.P., New concepts in antimalarial use and mode of action in dermatology (2007) Dermatology and Therapy, 20, pp. 160-174 Macfarlane, D.E., Manzel, L., Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds (1998) Journal of Immunology, 160, pp. 1122-1131 Jeong, J.Y., Jue, D.M., Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages (1997) Journal of Immunology, 158, pp. 4901-4907 Bondeson, J., Sundler, R., Antimalarial drugs inhibit phospholipase A2 activation and induction of interleukin 1beta and tumor necrosis factor alpha in macrophages: implications for their mode of action in rheumatoid arthritis (1998) General Pharmacology, 30, pp. 357-366 van den Borne, B.E., Dijkmans, B.A., de Rooij, H.H., le Cessie, S., Verweij, C.L., Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells (1997) Journal of Rheumatology, 24, pp. 55-60 Jeong, J.Y., Choi, J.W., Jeon, K.I., Jue, D.M., Chloroquine decreases cell-surface expression of tumour necrosis factor receptors in human histiocytic U-937 cells (2002) Immunology, 105, pp. 83-91 Legssyer, R., Josse, C., Piette, J., Ward, R.J., Crichton, R.R., Changes in function of iron-loaded alveolar macrophages after in vivo administration of desferrioxamine and/or chloroquine (2003) Journal of Inorganic Biochemistry, 94, pp. 36-42 Picot, S., Peyron, F., Donadille, A., Vuillez, J.P., Barbe, G., Ambroise-Thomas, P., Chloroquine-induced inhibition of the production of TNF, but not of IL-6, is affected by disruption of iron metabolism (1993) Immunology, 80, pp. 127-133 Weber, S.M., Levitz, S.M., Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism (2000) Journal of Immunology, 165, pp. 1534-1540 Goldman, F.D., Gilman, A.L., Hollenback, C., Kato, R.M., Premack, B.A., Rawlings, D.J., Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties (2000) Blood, 95, pp. 3460-3466 Sperber, K., Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells (1993) Journal of Rheumatology, 20, pp. 803-808