Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine
Abstract
Hydroxychloroquine (HCQ) is a lysosomotropic amine with cytotoxic properties. Here, we show that HCQ induces signs of lysosomal membrane permeabilization (LMP), such as the decrease in the lysosomal pH gradient and the release of cathepsin B from the lysosomal lumen, followed by signs of apoptosis including caspase activation, phosphatidylserine exposure, and chromatin condensation with DNA loss. HCQ also induces mitochondrial membrane permeabilization (MMP), as indicated by the insertion of Bax into mitochondrial membranes, the conformational activation of Bax within mitochondria, the release of cytochrome c from mitochondria, and the loss of the mitochondrial transmembrane potential. To determine the molecular order among these events, we introduced inhibitors of LMP (bafilomycin A(1)), MMP (Bcl-X(L), wild-type Bcl-2, mitochondrion-targeted Bcl-2, or viral mitochondrial inhibitor of apoptosis from cytomegalovirus), and caspases (Z-VAD.fmk) into the system. Our data indicate that caspase-independent MMP is rate-limiting for LMP-mediated caspase activation. Mouse embryonic fibroblasts lacking the expression of both Bax and Bak are resistant against hydroxychloroquine-induced apoptosis. Such Bax(-/-) Bak(-/-) cells manifest normal LMP, yet fail to undergo MMP and subsequent cell death. The data reported herein indicate that LMP does not suffice to trigger caspase activation and that Bax/Bak-dependent MMP is a critical step of LMP-induced cell death.
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In other experimental settings, lysosomes are permeabilized before mitochondria via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by activation of its pore-forming activity.
“In other experimental settings, however, lysosomes are permeabilized before mitochondria [752, 760, 761], via a mechanism that optionally involves BAX recruitment to the lysosomal membrane followed by the activation of its pore-forming activity [762–765].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [761]
Cites
Green, D. R., & Reed, J. C. (1998) · Science · doi:10.1126/science.281.5381.1309 · Cited by 8,998 · see citing works
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Wei, M. C., Zong, W.-X., Cheng, E. H.-Y., Lindsten, T., Panoutsakopoulou, V., Ross, A. J., Roth, K. A., MacGregor, G. R., Thompson, C. B., & Korsmeyer, S. J. (2001) · Science · doi:10.1126/science.1059108 · Cited by 3,988 · see citing works
Mitochondrial control of cell death
Kroemer, G., & Reed, J. C. (2000) · Nature Medicine · doi:10.1038/74994 · Cited by 3,103 · see citing works
Self-citationde Duve, C., & Wattiaux, R. (1966) · Annual Review of Physiology · doi:10.1146/annurev.ph.28.030166.002251 · Cited by 3,033 · cited 1× · see citing works
“…this paper reinforce the general idea that MMP is rate limiting for cell death induction (Boya et al., 2003), even when apoptosis has initially been triggered by permeabilizing the ‘suicide bags’, as lysosomes have been initially nick-named (De Duve and Wattiaux, 1966; Lockshin and Zakeri, 2001).”
BackgroundNicholson, D. W., & Thornberry, N. A. (1997) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(97)01085-2 · Cited by 2,430 · see citing works
Zamzami, N., Marchetti, P., Castedo, M., Decaudin, D., Macho, A., Hirsch, T., Susin, S. A., Petit, P. X., Mignotte, B., & Kroemer, G. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.2.367 · Cited by 1,567 · see citing works
Self-citationOrganelle-specific initiation of cell death pathways
Ferri, K. F., & Kroemer, G. (2001) · Nature Cell Biology · doi:10.1038/ncb1101-e255 · Cited by 1,455 · see citing works
Self-citationEnforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis
Gross, A., Jockel, J., Wei, M. C., & Korsmeyer, S. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.14.3878 · Cited by 1,086 · see citing works
Mitochondrio‐nuclear translocation of AIF in apoptosis and necrosis
Daugas, É., Susín, S. A., Zamzami, N., Ferri, K. F., Irinopoulou, T., Larochette, N., Prévost, M., Leber, B. F., Andrews, D. W., Penninger, J. M., et al. (2000) · The FASEB Journal · doi:10.1096/fasebj.14.5.729 · Cited by 776 · see citing works
Self-citationRequirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization
Lassus, P., Opitz-Araya, X., & Lazebnik, Y. A. (2002) · Science · doi:10.1126/science.1074721 · Cited by 719 · see citing works
Lysosomal Protease Pathways to Apoptosis
Stoka, V., Turk, B., Schendel, S. L., Kim, T., Cirman, T., Snipas, S. J., Ellerby, L., Bredesen, D. E., Freeze, H. H., Abrahamson, M., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008944200 · Cited by 673 · see citing works
Reed, J. C. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd726 · Cited by 640 · see citing works
Foghsgaard, L., Wissing, D., Mauch, D., Lademann, U. A., Bastholm, L., Boes, M. L., Elling, F., Leist, M., & Jäättelä, M. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.5.999 · Cited by 629 · see citing works
Regulated Targeting of BAX to Mitochondria
Goping, I. S., Gross, A., Lavoie, J. N., Nguyen, M., Jemmerson, R., Roth, K. A., Korsmeyer, S. J., & Shore, G. C. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.1.207 · Cited by 611 · see citing works
Marsden, V. S., O'Connor, L., O'Reilly, L. A., Silke, J., Metcalf, D., Ekert, P. G., Huang, D. C. S., Cecconi, F., Kuida, K., Tomaselli, K. J., et al. (2002) · Nature · doi:10.1038/nature01101 · Cited by 578 · see citing works
A novel assay to study autophagy: regulation of autophagosome vacuole size by amino acid deprivation
Munafó, D. B., & Colombo, M. I. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.20.3619 · Cited by 516 · see citing works
Mitochondria, the killer organelles and their weapons
Ravagnan, L., Roumier, T., & Kroemer, G. (2002) · Journal of Cellular Physiology · doi:10.1002/jcp.10111 · Cited by 484 · see citing works
Self-citationGriffiths, G. J., Dubrez, L., Morgan, C. P., Jones, N. A., Whitehouse, J., Corfe, B. M., Dive, C., & Hickman, J. A. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.144.5.903 · Cited by 479 · see citing works
Bax and Bak Coalesce into Novel Mitochondria-Associated Clusters during Apoptosis
Nechushtan, A., Smith, C. L., Lamensdorf, I., Yoon, S., & Youle, R. J. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.6.1265 · Cited by 477 · see citing works
Inbal, B., Bialik, S., Sabanay, I., Shani, G., & Kimchi, A. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200109094 · Cited by 476 · see citing works
Goldmacher, V. S., Bartle, L. M., Skaletskaya, A., Dionne, C. A., Kedersha, N., Vater, C. A., Han, J., Lutz, R. J., Watanabe, S., McFarland, E. D. C., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12536 · Cited by 425 · see citing works
Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins
Zamzami, N., Brenner, C., Marzo, I., Susín, S. A., & Kroemer, G. (1998) · Oncogene · doi:10.1038/sj.onc.1201989 · Cited by 414 · see citing works
Self-citationChemotherapy: targeting the mitochondrial cell death pathway
Debatin, K., Poncet, D., & Kroemer, G. (2002) · Oncogene · doi:10.1038/sj.onc.1206039 · Cited by 398 · see citing works
Self-citationRecommendations on screening for chloroquine and hydroxychloroquine retinopathy
Marmor, M. F., Carr, R. E., Easterbrook, M., Farjo, A. A., & Mieler, W. F. (2002) · Ophthalmology · doi:10.1016/s0161-6420(02)01168-5 · Cited by 371 · see citing works
Programmed cell death and apoptosis: origins of the theory
Lockshin, R. A., & Zakeri, Z. F. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35080097 · Cited by 361 · see citing works
Castedo, M., Hirsch, T., Susín, S. A., Zamzami, N., Marchetti, P., Macho, A., & Kroemer, G. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.2.512 · Cited by 350 · see citing works
Self-citationZhu, W., Cowie, A., Wasfy, G. W., Penn, L. Z., Leber, B. F., & Andrews, D. W. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00788.x · Cited by 327 · see citing works
Atractyloside‐induced release of cathepsin B, a protease with caspase‐processing activity
Vancompernolle, K., Herreweghe, F. V., PYNAERT, G. N., de Craen, M. V., Vos, K. J. D., Totty, N., Sterling, A., Fiers, W., Vandenabeele, P., & Grooten, J. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)01275-7 · Cited by 304 · see citing works
Quantitation of mitochondrial alterations associated with apoptosis
Castedo, M., Ferri, K. F., Roumier, T., Métivier, D., Zamzami, N., & Kroemer, G. (2002) · Journal of Immunological Methods · doi:10.1016/s0022-1759(02)00069-8 · Cited by 260 · see citing works
Self-citationThe adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal
Vieira, H. L., Belzacq, A.-S., Haouzi, D., Bernassola, F., Cohen, I., Jacotot, E., Ferri, K. F., El Hamel, C., Bartle, L. M., Melino, G., et al. (2001) · Oncogene · doi:10.1038/sj.onc.1204575 · Cited by 244 · cited 1× · see citing works
“Similarly, HeLa cells expressing the MMP inhibitor vMIA (viral mitochondrial inhibitor of apoptosis) (from cytomegalovirus) (Goldmacher et al., 1999; Vieira et al., 2001) were partially protected against the HCQ-driven MMP and PMP (Figure 6a).”
BackgroundSelf-citationXue, L., Fletcher, G. C., & Tolkovsky, A. M. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00100-2 · Cited by 230 · see citing works
Lysosomal destabilization in p53-induced apoptosis
Yuan, X., Li, W., Dalen, H., Lotem, J., Kama, R., Sachs, L., & Brunk, U. T. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092135599 · Cited by 226 · see citing works
Apoptosis Control in Syncytia Induced by the HIV Type 1–Envelope Glycoprotein Complex
Ferri, K. F., Jacotot, E. D., Blanco, J., Esté, J. A., Zamzami, N., Susín, S. A., Xie, Z., Brothers, G. M., Reed, J. C., Penninger, J. M., et al. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.8.1081 · Cited by 221 · see citing works
Self-citationBid acts on the permeability transition pore complex to induce apoptosis
Zamzami, N., Hamel, C. E., Maisse, C., Brenner, C., Muñoz-Pinedo, C., Belzacq, A.-S., Costantini, P., Vieira, H., Loeffler, M., Molle, G., et al. (2000) · Oncogene · doi:10.1038/sj.onc.1204030 · Cited by 178 · see citing works
Self-citationApoptosis: Mitochondrial Membrane Permeabilization – The (W)hole Story?
Zamzami, N., & Kroemer, G. (2003) · Current Biology · doi:10.1016/s0960-9822(02)01433-1 · Cited by 157 · see citing works
Self-citationTriggering caspase-independent cell death to combat cancer
Mathiasen, I. S., & Jäättelä, M. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02328-6 · Cited by 150 · see citing works
Cathepsin B-Mediated Activation of the Proinflammatory Caspase-11
Schotte, P., Criekinge, W. V., de Craen, M. V., Loo, G., Desmedt, M., Grooten, J., Cornelissen, M., Ridder, L. D., Vandekerckhove, J. S., Fiers, W., et al. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.9425 · Cited by 150 · see citing works
H+-translocating ATPase in Golgi apparatus
Moriyama, Y., & Nelson, N. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)51486-1 · Cited by 146 · see citing works
Castedo, M., Ferri, K. F., Blanco, J., Roumier, T., Larochette, N., Barretina, J. G., Amendola, A., Nardacci, R., Métivier, D., Esté, J. A., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.8.1097 · Cited by 145 · see citing works
Self-citationEndoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization
Boya, P., COHEN, I. R., Zamzami, N., Vieira, H. L. A., & Kroemer, G. (2002) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401006 · Cited by 139 · see citing works
Self-citationLevy-Strumpf, N., & Kimchi, A. (1998) · Oncogene · doi:10.1038/sj.onc.1202588 · Cited by 136 · see citing works
Annis, M. G., Zamzami, N., Zhu, W., Penn, L. Z., Kroemer, G., Leber, B. F., & Andrews, D. W. (2001) · Oncogene · doi:10.1038/sj.onc.1204288 · Cited by 126 · see citing works
Self-citationKitanaka, C. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.5.358 · Cited by 113 · see citing works
Chloroquine-Induced Neuronal Cell Death Is p53 and Bcl-2 Family-Dependent But Caspase-Independent
Zaidi, A. U., McDonough, J. S., Klocke, B. J., Latham, C. B., Korsmeyer, S. J., Flavell, R. A., Schmidt, R. E., & Roth, K. A. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.10.937 · Cited by 96 · see citing works
Roberg, K. B. (2001) · Laboratory Investigation · doi:10.1038/labinvest.3780222 · Cited by 91 · see citing works
Aillet, F., Masutani, H., Elbim, C., Raoul, H., Chêne, L., Nugeyre, M.-T., Payá, C. V., Barré‐Sinoussi, F., Gougerot‐Pocidalo, M., & Israël, N. (1998) · Journal of Virology · doi:10.1128/jvi.72.12.9698-9705.1998 · Cited by 74 · see citing works
Zhao, M., Eaton, J. W., & Brunk, U. T. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03185-4 · Cited by 64 · see citing works
Lai, J., Ho, L., Lu, K., Chang, D., Shaio, M., & Han, S. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.11.6914 · Cited by 48 · see citing works
Tantalizing Thanatos: unexpected links in death pathways
Cohen, I., Castedo, M., & Kroemer, G. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(02)02299-7 · Cited by 33 · see citing works
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationOxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis
Shimada, K., Crother, T. R., Karlin, J., Dagvadorj, J., Chiba, N., Chen, S., Ramanujan, V. K., Wolf, A. J., Vergnes, L., Ojcius, D. M., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.01.009 · Cited by 2,282 · see citing works
Inhibition of Macroautophagy Triggers Apoptosis
Boya, P., González‐Polo, R. A., Casares, N., Perfettini, J., Dessen, P., Larochette, N., Métivier, D., Meley, D., Souquère, S., Yoshimori, T., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.3.1025-1040.2005 · Cited by 1,629 · see citing works
Self-citationLysosomal membrane permeabilization in cell death
Boya, P., & Kroemer, G. (2008) · Oncogene · doi:10.1038/onc.2008.310 · Cited by 1,425 · see citing works
Self-citationAutophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment
Sui, X., Chen, R. B., Wang, Z., Huang, Z., Kong, N., Zhang, M., Han, W., Lou, F., Yang, J., Zhang, Q., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.350 · Cited by 1,209 · see citing works
Autophagy in malignant transformation and cancer progression
Galluzzi, L., Pietrocola, F., Bravo‐San Pedro, J. M., Amaravadi, R. K., Baehrecke, E. H., Cecconi, F., Codogno, P., Debnath, J., Gewirtz, D. A., Karantza, V., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490784 · Cited by 1,182 · see citing works
Self-citationRole of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells
Kanzawa, T., Germano, I. M., Komata, T., Ito, H., Kondo, Y., & Kondo, S. (2004) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401359 · Cited by 986 · see citing works
Cell Death Independent of Caspases: A Review
Bröker, L. E., Kruyt, F. A. E., & Giaccone, G. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-2223 · Cited by 899 · see citing works
Guicciardi, M. E., Leist, M., & Gores, G. J. (2004) · Oncogene · doi:10.1038/sj.onc.1207512 · Cited by 716 · see citing works
Apoptosis, autophagy, and more
Lockshin, R. A., & Zakeri, Z. F. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.04.011 · Cited by 701 · see citing works
Kinsey, C. G., Camolotto, S. A., Boespflug, A. M., Guillen, K. P., Foth, M., Truong, A., Schuman, S. S., Shea, J. E., Seipp, M. T., Yap, J. T., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0367-9 · Cited by 634 · see citing works
Cathepsin D—Many functions of one aspartic protease
Beneš, P., Větvička, V., & Fusek, M. (2008) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2008.02.008 · Cited by 640 · see citing works
Heid, M. E., Keyel, P. A., Kamga, C., Shiva, S., Watkins, S. C., & Salter, R. D. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301490 · Cited by 570 · see citing works
Apoptosis and autophagy: regulatory connections between two supposedly different processes
Thorburn, A. M. (2007) · APOPTOSIS · doi:10.1007/s10495-007-0154-9 · Cited by 555 · see citing works
The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death
González‐Polo, R. A., Boya, P., Pauleau, A., Jalil, A., Larochette, N., Souquère, S., Eskelinen, E., Pierron, G., Säftig, P., & Kroemer, G. (2005) · Journal of Cell Science · doi:10.1242/jcs.02447 · Cited by 525 · see citing works
Self-citationChloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies.
Solomon, V., & Lee, H.-Y. (2009) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2009.06.063 · Cited by 532 · see citing works
Heat shock proteins: essential proteins for apoptosis regulation
Lanneau, D., Brunet, M., Frisan, E., Solary, É., Fontenay, M., & Garrido, C. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00273.x · Cited by 502 · see citing works
Carew, J. S., Nawrocki, S. T., Kahue, C. N., Zhang, H., Yang, C., Chung, L., Houghton, J. A., Huang, P., Giles, F. J., & Cleveland, J. L. (2007) · Blood · doi:10.1182/blood-2006-10-050260 · Cited by 488 · see citing works
Hepatocyte Death: A Clear and Present Danger
Malhi, H., Guicciardi, M. E., & Gores, G. J. (2010) · Physiological Reviews · doi:10.1152/physrev.00061.2009 · Cited by 477 · see citing works
The role of mitochondria in NLRP3 inflammasome activation
Liu, Q., Zhang, D., Hu, D., Zhou, X., & Zhou, Y. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2018.09.010 · Cited by 475 · see citing works
Lysosomes and lysosomal cathepsins in cell death
Repnik, U., Stoka, V., Türk, V., & Turk, B. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.08.016 · Cited by 403 · see citing works
Droga-Mazovec, G., Bojič, L., Petelin, A., Ivanova, S., Romih, R., Repnik, U., Salvesen, G. S., Stoka, V., Turk, V., & Turk, B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802513200 · Cited by 399 · see citing works
Apoptosis and Necrosis in the Liver
Guicciardi, M. E., Malhi, H., Mott, J. L., & Gores, G. J. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120020 · Cited by 387 · see citing works
Cheng, G., Kong, R., Zhang, L., & Zhang, J. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02025.x · Cited by 345 · see citing works
Role of mitochondria as the gardens of cell death
Kim, R., Emi, M., & Tanabe, K. (2005) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-005-0111-7 · Cited by 328 · see citing works
Plantone, D., & Koudriavtseva, T. (2018) · Clinical Drug Investigation · doi:10.1007/s40261-018-0656-y · Cited by 305 · see citing works
Hombach‐Klonisch, S., Mehrpour, M., Shojaei, S., Harlos, C. H., Pitz, M. W., Hamaï, A., Siemianowicz, K., Likus, W., Wiecheć, E., Toyota, B. D., et al. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.10.017 · Cited by 290 · see citing works
O’Donovan, T. R., O’Sullivan, G. C., & McKenna, S. L. (2011) · Autophagy · doi:10.4161/auto.7.5.15066 · Cited by 281 · see citing works
Central role of mitochondria in drug-induced liver injury
Pessayre, D., Fromenty, B., Berson, A., Robin, M.-A., Lettéron, P., Moreau, R., & Mansouri, A. (2012) · Drug Metabolism Reviews · doi:10.3109/03602532.2011.604086 · Cited by 277 · see citing works
Maclean, K. H., Dorsey, F. C., Cleveland, J. L., & Kastan, M. B. (2007) · Journal of Clinical Investigation · doi:10.1172/jci33700 · Cited by 273 · see citing works
Hypoxic-Ischemic Encephalopathy in the Term Infant
Fatemi, A. S., Wilson, M. A., & Johnston, M. V. (2009) · Clinics in Perinatology · doi:10.1016/j.clp.2009.07.011 · Cited by 267 · see citing works
Inhibition of HSP70: A challenging anti-cancer strategy
Goloudina, A. R., Demidov, O. N., & Garrido, C. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.06.003 · Cited by 232 · see citing works
Autophagy in the eye: Development, degeneration, and aging
Boya, P., Esteban‐Martínez, L., Serrano‐Puebla, A., Gómez‐Sintes, R., & Villarejo‐Zori, B. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2016.08.001 · Cited by 231 · see citing works
Self-citationChloroquine and hydroxychloroquine in antitumor therapies based on autophagy-related mechanisms
Ferreira, P. M. P., de Sousa, R. W. R., Ferreira, J. R. D. O., Militão, G. C. G., & Bezerra, D. P. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105582 · Cited by 236 · see citing works
Targeting autophagy in disease: established and new strategies
Koçak, M., Erdi, S. E., Jorba, G., Maestro, I., Farrés, J., Kirkin, V., Martı́nez, A., & Pleß, O. (2021) · Autophagy · doi:10.1080/15548627.2021.1936359 · Cited by 229 · see citing works
Hamacher‐Brady, A., Stein, H., Turschner, S., Toegel, I., Mora-Rodríguez, R. A., Jennewein, N., Efferth, T., Eils, R., & Brady, N. R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.210047 · Cited by 230 · see citing works
Cathepsins: Key modulators of cell death and inflammatory responses
Conus, S., & Simon, H. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.07.041 · Cited by 228 · see citing works
Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy
Eng, C. H., Wang, Z., Tkach, D., Toral‐Barza, L., Ugwonali, S., Liu, S., Fitzgerald, S., George, E., Frias, E., Cochran, N. R., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515617113 · Cited by 228 · see citing works
Chloroquine and hydroxychloroquine for cancer therapy
Manic, G., Obrist, F., Kroemer, G., Vitale, I., & Galluzzi, L. (2014) · Molecular & Cellular Oncology · doi:10.4161/mco.29911 · Cited by 223 · see citing works
Self-citationChloroquine enhances human CD8 + T cell responses against soluble antigens in vivo
Accapezzato, D., Visco, V., Francavilla, V., Molette, C., Donato, T., Paroli, M., Mondelli, M. U., Doria, M., Torrisi, M. R., & Barnaba, V. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20051106 · Cited by 219 · see citing works
Erdal), D. H. K. (., Berndtsson, M., Castro, J., Brunk, U. T., Shoshan, M. C., & Linder, S. T. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408592102 · Cited by 218 · see citing works
Geng, Y., Kohli, L., Klocke, B. J., & Roth, K. A. (2010) · Neuro-Oncology · doi:10.1093/neuonc/nop048 · Cited by 217 · see citing works
Lysosomal cell death mechanisms in aging
Gómez-Sintes, R., Ledesma, M. D., & Boya, P. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.02.009 · Cited by 216 · see citing works
Self-citationAutophagy Modulation in Cancer: Current Knowledge on Action and Therapy
Marinković, M., Šprung, M., Buljubašić, M., & Novak, I. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/8023821 · Cited by 213 · see citing works
Protease signalling in cell death: caspases versus cysteine cathepsins
Turk, B., & Stoka, V. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.05.038 · Cited by 211 · see citing works
Serrano‐Puebla, A., & Boya, P. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12966 · Cited by 204 · see citing works
Self-citationBröker, L. E., Huisman, C., Span, S. W., Rodríguez, J. A., Kruyt, F. A. E., & Giaccone, G. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-3060 · Cited by 206 · see citing works
A review: the trend of progress about pH probes in cell application in recent years
Yue, Y., Huo, F., Lee, S., Yin, C., & Yoon, J. (2016) · The Analyst · doi:10.1039/c6an01942k · Cited by 200 · see citing works
Imaging small molecule-induced endosomal escape of siRNA
Rietz, H. D., Hedlund, H., Wilhelmson, S., Nordenfelt, P., & Wittrup, A. (2020) · Nature Communications · doi:10.1038/s41467-020-15300-1 · Cited by 203 · see citing works
Hydroxychloroquine: A multifaceted treatment in lupus
Costedoat-Chalumeau, N., Dunogué, B., Morel, N., Guern, V. L., & Guettrot-Imbert, G. (2014) · La Presse Médicale · doi:10.1016/j.lpm.2014.03.007 · Cited by 195 · see citing works
Combating apoptosis and multidrug resistant cancers by targeting lysosomes
Groth‐Pedersen, L., & Jäättelä, M. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.05.021 · Cited by 192 · see citing works
Methods for Assessing Autophagy and Autophagic Cell Death
Tasdemir, E., Galluzzi, L., Maiuri, M. C., Criollo, A., Vitale, I., Hangen, E., Modjtahedi, N., & Kroemer, G. (2008) · Methods in molecular biology · doi:10.1007/978-1-59745-157-4_3 · Cited by 194 · see citing works
Self-citationWei, Y., Zhou, F., Zhang, D., Chen, Q., & Xing, D. (2016) · Nanoscale · doi:10.1039/c5nr07785k · Cited by 191 · see citing works
Yue, W., Hamaï, A., Tonelli, G., Bauvy, C., Nicolas, V., Tharinger, H., Codogno, P., & Mehrpour, M. (2013) · Autophagy · doi:10.4161/auto.23997 · Cited by 187 · see citing works
Wang, F., Salvati, A. L., & Boya, P. (2018) · Open Biology · doi:10.1098/rsob.170271 · Cited by 182 · see citing works
Self-citationMechanisms of fenretinide-induced apoptosis
Hail, N., Kim, H. J., & Lotan, R. (2006) · APOPTOSIS · doi:10.1007/s10495-006-9289-3 · Cited by 182 · see citing works
Cathepsin L, target in cancer treatment?
Lankelma, J. M., Voorend, D. M., Barwari, T., Koetsveld, J., van der Spek, A. H., de Porto, A. P. N. A., van Rooijen, G., & Noorden, C. J. F. V. (2009) · Life Sciences · doi:10.1016/j.lfs.2009.11.016 · Cited by 182 · see citing works
Lysosomal–mitochondrial cross-talk during cell death
Repnik, U., & Turk, B. (2010) · Mitochondrion · doi:10.1016/j.mito.2010.07.008 · Cited by 178 · see citing works
AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics
Delavallée, L., Cabon, L., Galán‐Malo, P., Lorenzo, H. K., & Susín, S. A. (2011) · IUBMB Life · doi:10.1002/iub.432 · Cited by 177 · see citing works
Impact of ROS Generated by Chemical, Physical, and Plasma Techniques on Cancer Attenuation
Mitra, S., Nguyen, L. N., Akter, M., Park, G., Choi, E. H., & Kaushik, N. K. (2019) · Cancers · doi:10.3390/cancers11071030 · Cited by 176 · see citing works
Prorenin Receptor Is Essential for Normal Podocyte Structure and Function
Oshima, Y., Kinouchi, K., Ichihara, A., Sakoda, M., Kurauchi-Mito, A., Bokuda, K., Narita, T., Kurosawa, H., Sun-Wada, G.-H., Wada, Y., et al. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2011020202 · Cited by 173 · see citing works
Pro-survival autophagy and cancer cell resistance to therapy
Das, C. K., Mandal, M., & Kögel, D. (2018) · Cancer and Metastasis Reviews · doi:10.1007/s10555-018-9727-z · Cited by 169 · see citing works
Bafilomycin A1 Inhibits Chloroquine-Induced Death of Cerebellar Granule Neurons
Shacka, J. J., Klocke, B. J., Shibata, M., Uchiyama, Y., Datta, G., Schmidt, R. E., & Roth, K. A. (2006) · Molecular Pharmacology · doi:10.1124/mol.105.018408 · Cited by 164 · see citing works
Killing a cancer: what are the alternatives?
Kreuzaler, P. A., & Watson, C. J. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3264 · Cited by 162 · see citing works
Viral proteins targeting mitochondria: controlling cell death
Boya, P., Pauleau, A., Poncet, D., González‐Polo, R. A., Zamzami, N., & Kroemer, G. (2004) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2004.08.007 · Cited by 162 · see citing works
Self-citationApoptosis effector mechanisms: A requiem performed in different keys
Hail, N., Carter, B. Z., Konopleva, M. Y., & Andreeff, M. (2006) · APOPTOSIS · doi:10.1007/s10495-006-6712-8 · Cited by 156 · see citing works
Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death
Pivtoraiko, V. N., Stone, S. L., Roth, K. A., & Shacka, J. J. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2263 · Cited by 150 · see citing works
Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis
Ziegler, P. K., Bollrath, J., Pallangyo, C. K., Matsutani, T., Canli, Ö., Oliveira, T. D., Diamanti, M. A., Müller, N., Gamrekelashvili, J., Putoczki, T. L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.05.028 · Cited by 150 · see citing works
Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells
Kim, E. L., Wuestenberg, R., Rübsam, A., Schmitz-Salue, C., Warnecke, G., Bucker, E.-M., Pettkus, N., Speidel, D., Rohde, V., Schulz‐Schaeffer, W., et al. (2010) · Neuro-Oncology · doi:10.1093/neuonc/nop046 · Cited by 149 · see citing works
The aging lysosome: An essential catalyst for late-onset neurodegenerative diseases
Nixon, R. A. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140443 · Cited by 149 · see citing works
Lysosomal membrane permeabilization as a cell death mechanism in cancer cells
Serrano‐Puebla, A., & Boya, P. (2018) · Biochemical Society Transactions · doi:10.1042/bst20170130 · Cited by 148 · see citing works
Self-citationMultifaceted effects of hydroxychloroquine in human disease
Olsen, N. J., Schleich, M. A., & Karp, D. R. (2013) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2013.01.001 · Cited by 146 · see citing works
Lysosomal cysteine cathepsins: signaling pathways in apoptosis
Stoka, V., Türk, V., & Turk, B. (2007) · Biological Chemistry · doi:10.1515/bc.2007.064 · Cited by 141 · see citing works
Rodríguez‐Muela, N., Hernández‐Pinto, A. M., Serrano‐Puebla, A., García‐Ledo, L., Latorre, S., de la Rosa, E. J., & Boya, P. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.203 · Cited by 140 · see citing works
Self-citationLipids and lipid peroxidation products in the pathogenesis of age-related macular degeneration
Kopitz, J., Holz, F. G., Kaemmerer, E., & Schütt, F. (2004) · Biochimie · doi:10.1016/j.biochi.2004.09.029 · Cited by 140 · see citing works
Mitochondrial Involvement in Drug-Induced Liver Injury
Pessayre, D., Mansouri, A., Berson, A., & Fromenty, B. (2009) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-00663-0_11 · Cited by 142 · see citing works
The Endolysosomal System in Cell Death and SurvivalPreprint
Repnik, U., Česen, M. H., & Turk, B. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008755 · Cited by 137 · see citing works
Therapeutic potential of AIF-mediated caspase-independent programmed cell death
Lorenzo, H. K., & Susín, S. A. (2007) · Drug Resistance Updates · doi:10.1016/j.drup.2007.11.001 · Cited by 135 · see citing works
González‐Polo, R. A., Niso‐Santano, M., Ortiz‐Ortiz, M. A., Gómez-Martín, A., Morán, J. M., García-Rubio, L., Francisco‐Morcillo, J., Zaragoza, C., Soler, G., & Fuentes, J. M. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm040 · Cited by 135 · see citing works
Kaplan, N., Wang, J., Wray, B. D., Patel, P. A., Yang, W., Peng, H., & Lavker, R. M. (2019) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.19-27656 · Cited by 128 · see citing works
Use of LysoTracker dyes: A flow cytometric study of autophagy
Chikte, S., Panchal, N., & Warnes, G. (2013) · Cytometry Part A · doi:10.1002/cyto.a.22312 · Cited by 129 · see citing works
Immune Response Against Dying Tumor Cells
Zitvogel, L., Casares, N., Péquignot, M. O., Chaput, N., Albert, M. L., & Kroemer, G. (2004) · Advances in immunology · doi:10.1016/s0065-2776(04)84004-5 · Cited by 129 · see citing works
Self-citationKLF4 is a tumor suppressor in B-cell non-Hodgkin lymphoma and in classic Hodgkin lymphoma
Guan, H., Xie, L., Leithäuser, F., Floßbach, L., Möller, P., Wirth, T., & Ushmorov, A. (2010) · Blood · doi:10.1182/blood-2009-12-256446 · Cited by 128 · see citing works
Werneburg, N. W., Guicciardi, M. E., Bronk, S. F., Kaufmann, S. H., & Gores, G. J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705671200 · Cited by 126 · see citing works
Lysosomal membrane permeabilization during apoptosis ‐ involvement of Bax?
Kågedal, K., Johansson, A., Johansson, U., Heimlich, G., Roberg, K. B., Wang, N. S., Jürgensmeier, J. M., & Öllinger, K. M. (2005) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2005.00442.x · Cited by 124 · see citing works
Ghavami, S., Yeganeh, B., Stelmack, G. L., Kashani, H. H., Sharma, P. K., Cunnington, R. H., Rattan, S. G., Bathe, K. L., Klonisch, T. C., Dixon, I., et al. (2012) · Cell Death and Disease · doi:10.1038/cddis.2012.61 · Cited by 123 · see citing works
Cation trapping by cellular acidic compartments: Beyond the concept of lysosomotropic drugs
Marceau, F., Bawolak, M., Lodge, R., Bouthillier, J., Gagné-Henley, A., Gaudreault, R. C., & Morissette, G. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2011.12.004 · Cited by 121 · see citing works
Shao, X., Ding, Z., Zhou, W., Li, Y., Li, Z., Cui, H., Lin, X., Cao, G., Cheng, B., Sun, H., et al. (2021) · Nature Nanotechnology · doi:10.1038/s41565-021-00952-x · Cited by 120 · see citing works
Thomas, T. P., Majoros, I., Kotlyar, A., Mullen, D. G., Holl, M. M. B., & Baker, J. R. (2009) · Biomacromolecules · doi:10.1021/bm900683r · Cited by 120 · see citing works
Shimada, K., Crother, T. R., Karlin, J. N., Chen, S., Chiba, N., Ramanujan, V. K., Vergnes, L., Ojcius, D. M., & Arditi, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021477 · Cited by 118 · see citing works
Hsp70: Anti-apoptotic and Tumorigenic Protein
Rérole, A.-L., Jego, G., & Garrido, C. (2011) · Methods in Molecular Biology · doi:10.1007/978-1-61779-295-3_16 · Cited by 118 · see citing works
Rotenone Inhibits Autophagic Flux Prior to Inducing Cell Death
Mader, B. J., Pivtoraiko, V. N., Flippo, H. M., Klocke, B. J., Roth, K. A., Mangieri, L. R., & Shacka, J. J. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300145z · Cited by 118 · see citing works
Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies
Pascolo, S. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.12.017 · Cited by 116 · see citing works
Autophagy–lysosomal-associated neuronal death in neurodegenerative disease
Nixon, R. A. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02799-7 · Cited by 117 · see citing works
Apoptotic Pathways and Therapy Resistance in Human Malignancies
Viktorsson, K., Lewensohn, R., & Zhivotovsky, B. (2005) · Advances in cancer research · doi:10.1016/s0065-230x(05)94004-9 · Cited by 108 · see citing works
Lysosomal Cysteine Proteases: Structural Features and their Role in Apoptosis
Stoka, V., Turk, B., & Türk, V. (2005) · IUBMB Life · doi:10.1080/15216540500154920 · Cited by 106 · see citing works
Ferroquine, the next generation antimalarial drug, has antitumor activity
Kondratskyi, A., Kondratska, K., Abeele, F. V., Gordienko, D. V., Dubois, C., Toillon, R., Slomianny, C., Lemière, S., Delcourt, P., Dewailly, E., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16154-2 · Cited by 102 · see citing works
Dragowska, W. H., Weppler, S. A., Wang, J. C., Wong, L. Y., Kapanen, A. I., Rawji, J. S., Warburton, C., Qadir, M. A., Donohue, E., Roberge, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076503 · Cited by 100 · see citing works
Shacka, J., Klocke, B., Young, C., Shibata, M., Olney, J., Uchiyama, Y., Saftig, P., & Roth, K. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.5577-06.2007 · Cited by 97 · see citing works
Firat, E., Weyerbrock, A., Gaedicke, S., Grosu, A., & Niedermann, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047357 · Cited by 98 · see citing works
- Authors
- Boya, P., Gonzalez-Polo, R.-A., Poncet, D., Andreau, K., Vieira, H. L., Roumier, T., Perfettini, J.-L., & Kroemer, G.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Kroemer, Guido
- Venue
- Oncogene
- Published
- 2003-06-17
- Volume
- 22
- Issue
- 25
- Pages
- 3927-3936
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2073788301
- Cited by
- 385
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 16 · 2023: 7 · 2022: 17 · 2021: 19 · 2020: 23 · 2019: 19 · 2018: 25 · 2017: 15 · 2016: 20 · 2015: 26 · 2014: 11 · 2013: 26 · 2012: 19
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- hydroxychloroquine, lysosomal membrane permeabilization, mitochondrial membrane permeabilization, Bax, Bak, cytochrome c release, caspase activation, Bcl-xL, Bcl-2, mitochondrial membrane potential, mouse embryonic fibroblasts
- MeSH terms
- Amino Acid Chloromethyl Ketones, Animals, Anti-Bacterial Agents, Cell Line, Enzyme Activation, HeLa Cells, Humans, Hydroxychloroquine, Intracellular Membranes, Lysosomes, Membrane Proteins, Mitochondria, Permeability, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transfection, Signal Transduction, Cysteine Proteinase Inhibitors, Apoptosis, Mice, Knockout, Macrolides, Jurkat Cells, Proto-Oncogene Proteins c-bcl-2, Genes, bcl-2, Caspases, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, bcl-2-Associated X Protein, Mice, Rats
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