The anticancer agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes prosurvival autophagy by two mechanisms: Persistent induction of autophagosome synthesis and impairment of lysosomal integrity

Journal of Biological Chemistry

Volumn 289, Issue 48, 2014, Pages 33568-33589

  Gutierrez, Elaine ^a   Richardson, Des R ^a   Jansson, Patric J ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

CHELATION; CHEMICAL COMPOUNDS; DRUG PRODUCTS; IRON COMPOUNDS; REDOX REACTIONS;

ANTI-CANCER AGENTS; ANTI-PROLIFERATIVE ACTIVITIES; LYSOSOMAL INTEGRITY; LYSOSOMAL MEMBRANES; MECHANISM OF ACTION; N-ACETYLCYSTEINE; REDOX-ACTIVE IRON; SURVIVAL MECHANISMS;

CELL DEATH;

ACETYLCYSTEINE; ANTINEOPLASTIC AGENT; AUTOPHAGY PROTEIN 5; BECLIN 1; COPPER; DEFEROXAMINE; DI 2 PYRIDYLKETONE 4,4 DIMETHYL 3 THIOSEMICARBAZONE; IRON; MESSENGER RNA; MICROTUBULE ASSOCIATED PROTEIN 1; MICROTUBULE ASSOCIATED PROTEIN 1 LIGHT CHAIN 3; PROTEIN P62; UNCLASSIFIED DRUG; DI-2-PYRIDYLKETONE-4,4-DIMETHYL-3-THIOSEMICARBAZONE; MAP1LC3A PROTEIN, HUMAN; MICROTUBULE ASSOCIATED PROTEIN; SCAVENGER; SIDEROPHORE; THIOSEMICARBAZONE DERIVATIVE; TUMOR PROTEIN;

ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; AUTOLYSOSOME; AUTOPHAGOSOME; AUTOPHAGY; BREAST CANCER CELL LINE; COMPLEX FORMATION; CONTROLLED STUDY; DRUG CYTOTOXICITY; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; LYSOSOME; NUCLEOTIDE SEQUENCE; CELL SURVIVAL; DRUG EFFECTS; FEMALE; METABOLISM; NEOPLASMS; OXIDATION REDUCTION REACTION; PATHOLOGY; PHAGOSOME; TUMOR CELL LINE;

ACETYLCYSTEINE; ANTINEOPLASTIC AGENTS; AUTOPHAGY; CELL LINE, TUMOR; CELL SURVIVAL; COPPER; DEFEROXAMINE; FEMALE; FREE RADICAL SCAVENGERS; HUMANS; IRON; LYSOSOMES; MICROTUBULE-ASSOCIATED PROTEINS; NEOPLASM PROTEINS; NEOPLASMS; OXIDATION-REDUCTION; PHAGOSOMES; SIDEROPHORES; THIOSEMICARBAZONES;

EID: 84912098442     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.599480     Document Type: Article

References (99)

1. Kondo, Y., Kanzawa, T., Sawaya, R., and Kondo, S. (2005) The role of autophagy in cancer development and response to therapy. Nat. Rev. Cancer 5, 726-734
2. Kroemer, G., and Jäättelä, M. (2005) Lysosomes and autophagy in cell death control. Nat. Rev. Cancer 5, 886-897
3. Lum, J. J., DeBerardinis, R. J., Thompson, C. B. (2005) Autophagy in metazoans: cell survival in the land of plenty. Nat. Rev. Mol. Cell Biol. 6, 439-448
4. Mathew, R., Karantza-Wadsworth, V., and White, E. (2007) Role of autophagy in cancer. Nat. Rev. Cancer 7, 961-967
5. Kurz, T., Terman, A., Gustafsson, B., and Brunk, U. (2008) Lysosomes in iron metabolism, ageing and apoptosis. Histochem. Cell Biol. 129, 389-406
6. Yu, Z., Persson, H. L., Eaton, J. W., and Brunk, U. T. (2003) Intralysosomal iron: a major determinant of oxidant-induced cell death. Free Radic. Biol. Med. 34, 1243-1252
7. Persson, H. L., Yu, Z., Tirosh, O., Eaton, J. W., and Brunk, U. T. (2003) Prevention of oxidant-induced cell death by lysosomotropic iron chelators. Free Radic. Biol. Med. 34, 1295-1305
8. Kurz, T., Leake, A., Von Zglinicki, T., and Brunk, U. T. (2004) Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage. Biochem. J. 378, 1039-1045
9. Kalinowski, D. S., and Richardson, D. R. (2005) The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol. Rev. 57, 547-583
10. Buss, J. L., Greene, B. T., Turner, J., Torti, F. M., and Torti, S. V. (2004) Iron chelators in cancer chemotherapy. Curr. Top. Med. Chem. 4, 1623-1635
11. Le, N. T., and Richardson, D. R. (2002) The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim. Biophys. Acta 1603, 31-46
12. Buss, J. L., Torti, F. M., and Torti, S. V. (2003) The role of iron chelation in cancer therapy. Curr. Med. Chem. 10, 1021-1034
13. Blatt, J., and Stitely, S. (1987) Antineuroblastoma activity of desferoxamine in human cell lines. Cancer Res. 47, 1749-1750
14. Chaston, T. B., Lovejoy, D. B., Watts, R. N., and Richardson, D. R. (2003) Examination of the antiproliferative activity of iron chelators: multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin. Cancer Res. 9, 402-414
15. Donfrancesco, A., Deb, G., Dominici, C., Pileggi, D., Castello, M. A., and Helson, L. (1990) Effects of a single course of deferoxamine in neuroblastoma patients. Cancer Res. 50, 4929-4930
16. Donfrancesco, A., Deb, G., Dominici, C., Angioni, A., Caniglia, M., De Sio, L., Fidani, P., Amici, A., and Helson, L. (1992) Deferoxamine, cyclophosphamide, etoposide, carboplatin, and thiotepa (D-CECaT): a new cytoreductive chelation-chemotherapy regimen in patients with advanced neuroblastoma. Am. J. Clin. Oncol. 15, 319-322
17. Estrov, Z., Tawa, A., Wang, X. H., Dubé, I. D., Sulh, H., Cohen, A., Gelfand, E. W., and Freedman, M. H. (1987) In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood 69, 757-761
18. Selig, R. A., Madafiglio, J., Haber, M., Norris, M. D., White, L., and Stewart, B. W. (1993) Ferritin production and desferrioxamine cytotoxicity in human neuroblastoma cell lines. Anticancer Res. 13, 721-725
19. Richardson, D., Ponka, P., and Baker, E. (1994) The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell. Cancer Res. 54, 685-689
20. Yuan, J., Lovejoy, D. B., and Richardson, D. R. (2004) Novel di-2-pyridyl derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood 104, 1450-1458
21. Whitnall, M., Howard, J., Ponka, P., and Richardson, D. R. (2006)Aclass of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc. Natl. Acad. Sci. U.S.A. 103, 14901-14906
22. Rao, V. A., Klein, S. R., Agama, K. K., Toyoda, E., Adachi, N., Pommier, Y., and Shacter, E. B. (2009) The iron chelator Dp44mT causes DNA damage and selective inhibition of topoisomerase IIα in breast cancer cells. Cancer Res. 69, 948-957
23. Rao, V. A., Zhang, J., Klein, S. R., Espandiari, P., Knapton, A., Dickey, J. S., Herman, E., and Shacter, E. B. (2011) The iron chelator Dp44mT inhibits the proliferation of cancer cells but fails to protect from doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats. Cancer Chemother. Pharmacol. 68, 1125-1134
24. Liu, W., Xing, F., Iiizumi-Gairani, M., Okuda, H., Watabe, M., Pai, S. K., Pandey, P. R., Hirota, S., Kobayashi, A., Mo, Y.-Y., Fukuda, K., Li, Y., and Watabe, K. (2012) N-myc downstream regulated gene 1 modulates Wnt-β-catenin signalling and pleiotropically suppresses metastasis. EMBO Mol. Med. 4, 93-108
25. Jansson, P. J., Sharpe, P. C., Bernhardt, P. V., and Richardson, D. R. (2010) Novel thiosemicarbazones of the ApT and DpT Series and their copper complexes: identification of pronounced redox activity and characterization of their antitumor activity. J. Med. Chem. 53, 5759-5769
26. Lovejoy, D. B., Sharp, D. M., Seebacher, N., Obeidy, P., Prichard, T., Stefani, C., Basha, M. T., Sharpe, P. C., Jansson, P. J., Kalinowski, D. S., Bernhardt, P. V., and Richardson, D. R. (2012) Novel second-generation di-2-pyridylketone thiosemicarbazones show synergism with standard chemotherapeutics and demonstrate potent activity against lung cancer xenografts after oral and intravenous administration in vivo. J. Med. Chem. 55, 7230-7244
27. Lovejoy, D. B., Jansson, P. J., Brunk, U. T., Wong, J., Ponka, P., and Richardson, D. R. (2011) Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes. Cancer Res. 71, 5871-5880
28. Gaál, A., Orgován, G., Polgári, Z., Réti, A., Mihucz, V. G., Bo{combining double acute accent}sze, S., Szoboszlai, N., and Streli, C. (2014) Complex forming competition and invitro toxicity studies on the applicability of di-2-pyridylketone-4,4,-di-methyl-3-thiosemicarbazone (Dp44mT) as a metal chelator. J. Inorg. Biochem. 130, 52-58
29. Kurz, T., Gustafsson, B., and Brunk, U. T. (2006) Intralysosomal iron chelation protects against oxidative stress-induced cellular damage. FEBS J. 273, 3106-3117
30. Richardson, D. R., and Milnes, K. (1997) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents II: the mechanism of action of ligands derived from salicylaldehyde benzoyl hydrazone and 2-hydroxy-1-naphthylaldehyde benzoyl hydrazone. Blood 89, 3025-3038
31. Liu, D., Yang, Y., Liu, Q., and Wang, J. (2011) Inhibition of autophagy by 3-MA potentiates cisplatin-induced apoptosis in esophageal squamous cell carcinoma cells. Med. Oncol. 28, 105-111
32. Voss, V., Senft, C., Lang, V., Ronellenfitsch, M. W., Steinbach, J. P., Seifert, V., and Kögel, D. (2010) The pan-Bcl-2 Inhibitor (-)-gossypol triggers autophagic cell death in malignant glioma. Mol. Cancer Res. 8, 1002-1016
33. Kanzawa, T., Germano, I. M., Komata, T., Ito, H., Kondo, Y., and Kondo, S. (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 11, 448-457
34. Bellodi, C., Lidonnici, M. R., Hamilton, A., Helgason, G. V., Soliera, A. R., Ronchetti, M., Galavotti, S., Young, K. W., Selmi, T., Yacobi, R., Van Etten, R. A., Donato, N., Hunter, A., Dinsdale, D., Tirrò, E., Vigneri, P., Nicotera, P., Dyer, M. J., Holyoake, T., Salomoni, P., and Calabretta, B. (2009) Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J. Clin. Investig. 119, 1109-1123
35. Chen, Y., McMillan-Ward, E., Kong, J., Israels, S. J., and Gibson, S. B. (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ. 15, 171-182
36. Gonzalez, P., Mader, I., Tchoghandjian, A., Enzenmüller, S., Cristofanon, S., Basit, F., Debatin, K.-M., and Fulda, S. (2012) Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process. Cell Death Differ. 19, 1337-1346
37. Wong, V. K., Li, T., Law, B. Y., Ma, E. D., Yip, N. C., Michelangeli, F., Law, C. K., Zhang, M. M., Lam, K. Y., Chan, P. L., and Liu, L. (2013) Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells. Cell Death Dis. 4, e720
38. Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C. B., and Tsujimoto, Y. (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat. Cell Biol. 6, 1221-1228
39. Richardson, D. R., Sharpe, P. C., Lovejoy, D. B., Senaratne, D., Kalinowski, D. S., Islam, M., and Bernhardt, P. V. (2006) Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity. J. Med. Chem. 49, 6510-6521
40. Kalinowski, D. S., Sharpe, P. C., Bernhardt, P. V., and Richardson, D. R. (2007) Design, synthesis, and characterization of new iron chelators with anti-proliferative activity: structure-activity relationships of novel thiohydrazone analogues. J. Med. Chem. 50, 6212-6225
41. Richardson, D. R., Tran, E. H., and Ponka, P. (1995) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood 86, 4295-4306
42. Gao, J., and Richardson, D. R. (2001) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression. Blood 98, 842-850
43. Le, N. T., and Richardson, D. R. (2004) Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood 104, 2967-2975
44. Chen, Z., Zhang, D., Yue, F., Zheng, M., Kovacevic, Z., and Richardson, D. R. (2012) The iron chelators Dp44mT and DFO inhibit TGFβ-induced epithelial-mesenchymal transition via up-regulation of N-myc downstream-regulated gene 1 (NDRG1). J. Biol. Chem. 287, 17016-17028
45. Esteve, J. M., and Knecht, E. (2011) Mechanisms of autophagy and apoptosis: recent developments in breast cancer cells. World J. Biol. Chem. 2, 232-238
46. Samaddar, J. S., Gaddy, V. T., Duplantier, J., Thandavan, S. P., Shah, M., Smith, M. J., Browning, D., Rawson, J., Smith, S. B., Barrett, J. T., and Schoenlein, P. V. (2008) A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. Mol. Cancer Ther. 7, 2977-2987
47. Schoenlein, P. V., Periyasamy-Thandavan, S., Samaddar, J. S., Jackson, W. H., and Barrett, J. T. (2009) Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance. Autophagy 5, 400-403
48. Brooks, S. C., Locke, E. R., and Soule, H. D. (1973) Estrogen receptor in a human cell line (MCF-7) from breast carcinoma. J. Biol. Chem. 248, 6251-6253
49. Mizushima, N., Yoshimori, T., and Levine, B. (2010) Methods in mammalian autophagy research. Cell 140, 313-326
50. Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., and Aguirre-Ghiso, J. A. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445-544
51. Yang, Z. J., Chee, C. E., Huang, S., and Sinicrope, F. A. (2011) The role of autophagy in cancer: therapeutic implications. Mol. Cancer Ther. 10, 1533-1541
52. Quach, P., Gutierrez, E., Basha, M. T., Kalinowski, D. S., Sharpe, P. C., Lovejoy, D. B., Bernhardt, P. V., Jansson, P. J., and Richardson, D. R. (2012) Methemoglobin formation by triapine, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and other anticancer thiosemicarbazones: identification of novel thiosemicarbazones and therapeutics that prevent this effect. Mol. Pharmacol. 82, 105-114
53. Yamamoto, A., Tagawa, Y., Yoshimori, T., Moriyama, Y., Masaki, R., and Tashiro, Y. (1998) Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell Line, H-4-II-E cells. Cell Struct. Funct. 23, 33-42
54. Sahni, S., Bae, D. H., Lane, D. J., Kovacevic, Z., Kalinowski, D. S., Jansson, P. J., and Richardson, D. R. (2014) The metastasis suppressor, N-myc downstream-regulated gene 1 (NDRG1), inhibits stress-induced autophagy in cancer cells. J. Biol. Chem. 289, 9692-9709
55. Bjørkøy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., Stenmark, H., and Johansen, T. (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171, 603-614
56. Puissant, A., Robert, G., Fenouille, N., Luciano, F., Cassuto, J.-P., Raynaud, S., and Auberger, P. (2010) Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 70, 1042-1052
57. Robert, G., Ben Sahra, I., Puissant, A., Colosetti, P., Belhacene, N., Gounon, P., Hofman, P., Bost, F., Cassuto, J.-P., and Auberger, P. (2009) Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. PLoS ONE 4, e7889
58. Sawicki, S. G., and Godman, G. C. (1971) On the differential cytotoxicity of actinomycin D. J. Cell Biol. 50, 746-761
59. Zhang, Y., Tang, Z. H., Ren, Z., Qu, S. L., Liu, M. H., Liu, L. S., and Jiang, Z. S. (2013) Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases. Mol. Cell. Biol. 33, 1104-1113
60. Predmore, B. L., Lefer, D. J., and Gojon, G. (2012) Hydrogen sulfide in biochemistry and medicine. Antioxid. Redox Signal. 17, 119-140
61. Aruoma, O. I., Halliwell, B., Hoey, B. M., and Butler, J. (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic. Biol. Med. 6, 593-597
62. Samuni, Y., Goldstein, S., Dean, O. M., and Berk, M. (2013) The chemistry and biological activities of N-acetylcysteine. Biochim. Biophys. Acta 1830, 4117-4129
63. Yu, H., Zhou, Y., Lind, S. E., and Ding, W.-Q. (2009) Clioquinol targets zinc to lysosomes in human cancer cells. Biochem. J. 417, 133-139
64. Paglin, S., Hollister, T., Delohery, T., Hackett, N., McMahill, M., Sphicas, E., Domingo, D., and Yahalom, J. (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res. 61, 439-444
65. Brunk, U. T., Dalen, H., Roberg, K., and Hellquist, H. B. (1997) Photooxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts. Free Radic. Biol. Med. 23, 616-626
66. Farkas, E., Csoka, H., Micera, G., and Dessi, A. (1997) Copper(II), nickel(II), zinc(II), and molybdenum(VI) complexes of desferrioxamine B in aqueous solution. J. Inorg. Biochem. 65, 281-286
67. Bolte, S., and Cordelières, F. P. (2006) A guided tour into subcellular colocalization analysis in light microscopy. J. Microsc. 224, 213-232
68. Manders, E. M., Verbeek, F. J., and Aten, J. A. (1993) Measurement of co-localization of objects in dual-colour confocal images. J. Microsc. 169, 375-382
69. Yelamanchili, S. V., Chaudhuri, A. D., Flynn, C. T., and Fox, H. S. (2011) Upregulation of cathepsin D in the caudate nucleus of primates with experimental parkinsonism. Mol. Neurodegener. 6, 52
70. Eskelinen, E.-L. (2006) Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol. Aspects Med. 27, 495-502
71. Tasdemir, E., Maiuri, M. C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., Nannmark, U., Samara, C., Pinton, P., Vicencio, J. M., Carnuccio, R., Moll, U. M., Madeo, F., Paterlini-Brechot, P., Rizzuto, R., Szabadkai, G., Pierron, G., Blomgren, K., Tavernarakis, N., Codogno, P., Cecconi, F., and Kroemer, G. (2008) Regulation of autophagy by cytoplasmic p53. Nat. Cell Biol. 10, 676-687
72. Kenific, C. M., Thorburn, A., and Debnath, J. (2010) Autophagy and metastasis: another double-edged sword. Curr. Opin. Cell Biol. 22, 241-245
73. White, E., and DiPaola, R. S. (2009) The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15, 5308-5316
74. Luo, S., and Rubinsztein, D. C. (2007) Atg5 and Bcl-2 provide novel insights into the interplay between apoptosis and autophagy. Cell Death Differ. 14, 1247-1250
75. Noulsri, E., Richardson, D. R., Lerdwana, S., Fucharoen, S., Yamagishi, T., Kalinowski, D. S., and Pattanapanyasat, K. (2009) Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells. Am. J. Hematol. 84, 170-176
76. Raisova, M., Hossini, A. M., Eberle, J., Riebeling, C., Wieder, T., Sturm, I., Daniel, P. T., Orfanos, C. E., and Geilen, C. C. (2001) The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J. Invest. Dermatol. 117, 333-340
77. Yousefi, S., Perozzo, R., Schmid, I., Ziemiecki, A., Schaffner, T., Scapozza, L., Brunner, T., and Simon, H.-U. (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat. Cell Biol. 8, 1124-1132
78. Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X. H., Mizushima, N., Packer, M., Schneider, M. D., and Levine, B. (2005) Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927-939
79. Asano, T., Komatsu, M., Yamaguchi-Iwai, Y., Ishikawa, F., Mizushima, N., and Iwai, K. (2011) Distinct mechanisms of ferritin delivery to lysosomes in iron-depleted and iron-replete cells. Mol. Cell. Biol. 31, 2040-2052
80. De Domenico, I., Ward, D. M., and Kaplan, J. (2009) Specific iron chelators determine the route of ferritin degradation. Blood 114, 4546-4551
81. Lloyd, J. B., Cable, H., and Rice-Evans, C. (1991) Evidence that desferrioxamine cannot enter cells by passive diffusion. Biochem. Pharmacol. 41, 1361-1363
82. Doulias, P.-T., Christoforidis, S., Brunk, U. T., and Galaris, D. (2003) Endosomal and lysosomal effects of desferrioxamine: protection of HeLa cells from hydrogen peroxide-induced DNA damage and induction of cell-cycle arrest. Free Radic. Biol. Med. 35, 719-728
83. Persson, H. L., and Richardson, D. R. (2005) Iron-binding drugs targeted to lysosomes: a potential strategy to treat inflammatory lung disorders. Expert Opin. Investig. Drugs 14, 997-1008
84. Jeong, J., and Levine, R. L. (2006) Desferrioxamine is both an iron chelator and a lysosomotropic amine. FASEB J. 20, A49
85. Dorer, F. E., Lentz, K. E., Kahn, J. R., Levine, M., and Skeggs, L. T. (1978) A comparison of the substrate specificities of cathepsin D and pseudorenin. J. Biol. Chem. 253, 3140-3142
86. Cooper, G. M. (1997) Lysosomes. in The Cell: A Molecular Approach (Fitzgerald, P. J., and Sinauer, A. D., eds), pp. 379-384, 2nd Ed., Sinauer Associates, Sunderland, MA
87. Qadir, M. A., Kwok, B., Dragowska, W. H., To, K. H., Le, D., Bally, M. B., and Gorski, S. (2008) Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Res. Treat. 112, 389-403
88. Bursch, W., Ellinger, A., Kienzl, H., Török, L., Pandey, S., Sikorska, M., Walker, R., and Hermann, R. S. (1996) Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 17, 1595-1607
89. Chen, Y., Schindler, M., and Simon, S. M. (1999) A mechanism for tamoxifen-mediated inhibition of acidification. J. Biol. Chem. 274, 18364-18373
90. Altan, N., Chen, Y., Schindler, M., and Simon, S. M. (1999) Tamoxifen inhibits acidification in cells independent of the estrogen receptor. Proc. Natl. Acad. Sci. U.S.A. 96, 4432-4437
91. Hwang, J. J., Kim, H. N., Kim, J., Cho, D.-H., Kim, M. J., Kim, Y.-S., Kim, Y., Park, S.-J., and Koh, J.-Y. (2010) Zinc(II) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line. BioMetals 23, 997-1013
92. Ford, C. H., Al-Bader, M., Al-Ayadhi, B., and Francis, I. (2011) Reassessment of estrogen receptor expression in human breast cancer cell lines. Anticancer Res. 31, 521-527
93. Scherz-Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., and Elazar, Z. (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26, 1749-1760
94. Kiffin, R., Bandyopadhyay, U., and Cuervo, A. M. (2006) Oxidative stress and autophagy. Antioxid. Redox Signal. 8, 152-162
95. Eisenberg-Lerner, A., Bialik, S., Simon, H.-U., and Kimchi, A. (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 16, 966-975
96. Mariño, G., Niso-Santano, M., Baehrecke, E. H., and Kroemer, G. (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 15, 81-94
97. Lamparska-Przybysz, M., Gajkowska, B., and Motyl, T. (2005) Cathepsins and BID are involved in the molecular switch between apoptosis and autophagy in breast cancer MCF-7 cells exposed to camptothecin. J. Physiol. Pharmacol. 56, 159-179
98. Wirawan, E., Vande Walle, L., Kersse, K., Cornelis, S., Claerhout, S., Vanoverberghe, I., Roelandt, R., De Rycke, R., Verspurten, J., Declercq, W., Agostinis, P., Vanden Berghe, T., Lippens, S., and Vandenabeele, P. (2010) Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 1, e18
99. Betin, V. M., and Lane, J. D. (2009) Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis. J. Cell Sci. 122, 2554-2566