Application and interpretation of current autophagy inhibitors and activators

Acta Pharmacologica Sinica

Volumn 34, Issue 5, 2013, Pages 625-635

  Yang, Ya Ping ^a   Hu, Li Fang ^a   Zheng, Hui Fen ^a   Mao, Cheng Jie ^a   Hu, Wei Dong ^a   Xiong, Kang Ping ^a   Wang, Fen ^a   Liu, Chun Feng ^a  

^a SOOCHOW UNIVERSITY   (China)

Author keywords

autophagy; cancer; cycloheximide; ER stress inducer; LiCl; lysosomal lumen alkalizer; neurodegenerative diseases; PI3K inhibitor; Rack1 protein; rapamycin

Indexed keywords

AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; AUTOPHAGY ACTIVATOR; AUTOPHAGY INHIBITOR; AUTOPHAGY PROTEIN 5; BREFELDIN A; CALPASTATIN; CARBAMAZEPINE; CELL PROTEIN; CYTOPLASM PROTEIN; EVEROLIMUS; LITHIUM CHLORIDE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PENITREM A; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEASOME; PROTEIN ATG12; PROTEIN ATG8; PROTEIN ATG9; RAPAMYCIN; TEMSIROLIMUS; THAPSIGARGIN; TREHALOSE; TUNICAMYCIN; UBIQUITIN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALPROIC ACID; XESTOSPONGIN B;

APOPTOSIS; AUTOPHAGOSOME; AUTOPHAGY; BIPOLAR DISORDER; CARDIOVASCULAR DISEASE; CELL ORGANELLE; DEGENERATIVE DISEASE; DIABETES MELLITUS; DRUG MECHANISM; ENDOPLASMIC RETICULUM STRESS; HUMAN; INFECTION; INFLAMMATORY DISEASE; LYSOSOME; MANTLE CELL LYMPHOMA; NEOPLASM; NONHUMAN; REVIEW;

ANIMALS; AUTOPHAGY; DRUG DISCOVERY; HUMANS; NEOPLASMS; NEURODEGENERATIVE DISEASES;

EID: 84877609418     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1038/aps.2013.5     Document Type: Review

References (125)

1. Yang YP, Liang ZQ, Gu ZL, Qin ZH. Molecular mechanism and regulation of autophagy. Acta Pharmacol Sin 2005; 26: 1421-34.
2. Meijer AJ, Codogno P. Autophagy: regulation and role in disease. Crit Rev Clin Lab Sci 2009; 46: 210-40.
3. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132: 27-42.
4. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, et al. A unified nomenclature for yeast autophagy-related genes. Dev Cell 2003; 5: 539-45.
5. Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2001; 2: 211-6.
6. Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011; 27: 107-32.
7. Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2001; 2: 330-5.
8. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999; 402: 672-6.
9. Weber JD, Gutmann DH. Deconvoluting mTOR biology. Cell Cycle 2012; 11: 236-48.
10. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-84.
11. Sarkar S, Ravikumar B, Floto RA, Rubinsztein DC. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine- expanded huntingtin and related proteinopathies. Cell Death Differ 2009; 16: 46-56.
12. Chu CT. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol 2006; 65: 423-32.
13. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003; 115: 727-38.
14. Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS, et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 2010; 29: 969-80.
15. Lee JY, Yao TP. Quality control autophagy: A joint effort of ubiquitin, protein deacetylase and actin cytoskeleton. Autophagy 2010; 6: 555-7.
16. Su M, Shi JJ, Yang YP, Li J, Zhang YL, Chen J, et al. HDAC6 regulates aggresome-autophagy degradation pathway of alpha-synuclein in response to MPP+-induced stress. J Neurochem 2011; 117: 112-20.
17. Cai ZL, Shi JJ, Yang YP, Cao BY, Wang F, Huang JZ, et al. MPP+ impairs autophagic clearance of alpha-synuclein by impairing the activity of dynein. Neuroreport 2009; 20: 569-73.
18. Seglen PO, Gordon PB. Amino acid control of autophagic sequestration and protein degradation in isolated rat hepatocytes. J Cell Biol 1984; 99: 435-44.
19. Mitchener JS, Shelburne JD, Bradford WD, Hawkins HK. Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. Am J Pathol 1976; 83: 485-92.
20. Chan LL, Shen D, Wilkinson AR, Patton W, Lai N, Chan E, et al. A novel image-based cytometry method for autophagy detection in living cells. Autophagy 2012; 8: 1371-82.
21. Konorov SO, Jardon MA, Piret JM, Blades MW, Turner RF. Raman microspectroscopy of live cells under autophagy-inducing conditions. Analyst 2012; 137: 4662-8.
22. Erdi B, Nagy P, Zvara A, Varga A, Pircs K, Menesi D, et al. Loss of the starvation-induced gene Rack1 leads to glycogen deficiency and impaired autophagic responses in Drosophila. Autophagy 2012; 8: 1124-35.
23. Yin JJ, Li YB, Wang Y, Liu GD, Wang J, Zhu XO, et al. The role of autophagy in endoplasmic reticulum stress-induced pancreatic beta cell death. Autophagy 2012; 8: 158-64.
24. Kim DS, Li B, Rhew KY, Oh HW, Lim HD, Lee W, et al. The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts. Arch Pharm Res 2012; 35: 1269-78.
25. Ciechomska IA, Gabrusiewicz K, Szczepankiewicz AA, Kaminska B. Endoplasmic reticulum stress triggers autophagy in malignant glioma cells undergoing cyclosporine A-induced cell death. Oncogene 2012; May 14 Epub ahead of print. doi: 10.1038/onc.2012.174.
26. Zoppino FC, Militello RD, Slavin I, Alvarez C, Colombo MI. Autophagosome formation depends on the small GTPase Rab1 and functional ER exit sites. Traffic 2010; 11: 1246-61.
27. Qin L, Wang Z, Tao L, Wang Y. ER stress negatively regulates AKT/ TSC/mTOR pathway to enhance autophagy. Autophagy 2010; 6: 239-47.
28. Kim DS, Kim JH, Lee GH, Kim HT, Lim JM, Chae SW, et al. p38 Mitogen-activated protein kinase is involved in endoplasmic reticulum stress-induced cell death and autophagy in human gingival fibroblasts. Biol Pharm Bull 2010; 33: 545-9.
29. Petrovski G, Das S, Juhasz B, Kertesz A, Tosaki A, Das DK. Cardioprotection by endoplasmic reticulum stress-induced autophagy. Antioxid Redox Signal 2011; 14: 2191-200.
30. Gordon PB, Holen I, Fosse M, Rotnes JS, Seglen PO. Dependence of hepatocytic autophagy on intracellularly sequestered calcium. J Biol Chem 1993; 268: 26107-12.
31. Ganley IG, Wong PM, Gammoh N, Jiang X. Distinct autophagosomallysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell 2011; 42: 731-43.
32. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrientsensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-75.
33. Tanemura M, Ohmura Y, Deguchi T, Machida T, Tsukamoto R, Wada H, et al. Rapamycin causes upregulation of autophagy and impairs islets function both in vitro and in vivo. Am J Transplant 2012; 12: 102-14.
34. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther 2007; 82: 381-8.
35. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17: 596-603.
36. Hall MN. mTOR-what does it do. Transplant Proc 2008; 40: S5-8.
37. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36: 585-95.
38. Galimberti S, Petrini M. Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma. Cancer Manag Res 2010; 2: 181-9.
39. Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005; 16: 525-37.
40. Floto RA, Sarkar S, Perlstein EO, Kampmann B, Schreiber SL, Rubinsztein DC. Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages. Autophagy 2007; 3: 620-2.
41. Sarkar S, Perlstein EO, Imarisio S, Pineau S, Cordenier A, Maglathlin RL, et al. Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol 2007; 3: 331-8.
42. Tian Y, Bustos V, Flajolet M, Greengard P. A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway. FASEB J 2011; 25: 1934-42.
43. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem 2007; 282: 5641-52.
44. Kruger U, Wang Y, Kumar S, Mandelkow EM. Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging 2012; 33: 2291-305.
45. Aguib Y, Heiseke A, Gilch S, Riemer C, Baier M, Schatzl HM, et al. Autophagy induction by trehalose counteracts cellular prion infection. Autophagy 2009; 5: 361-9.
46. Ravikumar B, Berger Z, Vacher C, O'Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006; 15: 1209-16.
47. Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005; 170: 1101-11.
48. Shimada K, Motoi Y, Ishiguro K, Kambe T, Matsumoto SE, Itaya M, et al. Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion. Neurobiol Dis 2012; 46: 101-8.
49. Atack JR, Cook SM, Watt AP, Fletcher SR, Ragan CI. In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330. J Neurochem 1993; 60: 652-8.
50. Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010; 329: 229-32.
51. Fu J, Shao CJ, Chen FR, Ng HK, Chen ZP. Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines. Neuro Oncol 2010; 12: 328-40.
52. Arico S, Petiot A, Bauvy C, Dubbelhuis PF, Meijer AJ, Codogno P, et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem 2001; 276: 35243-6.
53. Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P. Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000; 275: 992-8.
54. Scarlatti F, Bauvy C, Ventruti A, Sala G, Cluzeaud F, Vandewalle A, et al. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem 2004; 279: 18384-91.
55. Ohwada J, Ebiike H, Kawada H, Tsukazaki M, Nakamura M, Miyazaki T, et al. Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799. Bioorg Med Chem Lett 2011; 21: 1767-72.
56. Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011; 10: 2426-36.
57. Wallin JJ, Guan J, Prior WW, Lee LB, Berry L, Belmont LD, et al. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo. Clin Cancer Res 2012; 18: 3901-11.
58. Criollo A, Maiuri MC, Tasdemir E, Vitale I, Fiebig AA, Andrews D, et al. Regulation of autophagy by the inositol trisphosphate receptor. Cell Death Differ 2007; 14: 1029-39.
59. Martinet W, De Meyer GR, Herman AG, Kockx MM. Amino acid deprivation induces both apoptosis and autophagy in murine C2C12 muscle cells. Biotechnol Lett 2005; 27: 1157-63.
60. Kawakami T, Inagi R, Takano H, Sato S, Ingelfinger JR, Fujita T, et al. Endoplasmic reticulum stress induces autophagy in renal proximal tubular cells. Nephrol Dial Transplant 2009; 24: 2665-72.
61. Ding WX, Ni HM, Gao W, Hou YF, Melan MA, Chen X, et al. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J Biol Chem 2007; 282: 4702-10.
62. Bray K, Mathew R, Lau A, Kamphorst JJ, Fan J, Chen J, et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLOS ONE 2012; 7: e41831.
63. Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC. Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 2010; 133: 93-104.
64. Cao C, Subhawong T, Albert JM, Kim KW, Geng L, Sekhar KR, et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 2006; 66: 10040-7.
65. Crazzolara R, Bradstock KF, Bendall LJ. RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. Autophagy 2009; 5: 727-8.
66. Lin CI, Whang EE, Donner DB, Du J, Lorch J, He F, et al. Autophagy induction with RAD001 enhances chemosensitivity and radiosensitivity through Met inhibition in papillary thyroid cancer. Mol Cancer Res 2010; 8: 1217-26.
67. Xiong N, Jia M, Chen C, Xiong J, Zhang Z, Huang J, et al. Potential autophagy enhancers attenuate rotenone-induced toxicity in SHSY5Y. Neuroscience 2011; 199: 292-302.
68. Kim H, Bernard ME, Flickinger J, Epperly MW, Wang H, Dixon TM, et al. The autophagy-inducing drug carbamazepine is a radiation protector and mitigator. Int J Radiat Biol 2011; 87: 1052-60.
69. Zeng X, Overmeyer JH, Maltese WA. Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J Cell Sci 2006; 119: 259-70.
70. Zhang L, Yu J, Pan H, Hu P, Hao Y, Cai W, et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci U S A 2007; 104: 19023-8.
71. Pedrozo Z, Sanchez G, Torrealba N, Valenzuela R, Fernandez C, Hidalgo C, et al. Calpains and proteasomes mediate degradation of ryanodine receptors in a model of cardiac ischemic reperfusion. Biochim Biophys Acta 2010; 1802: 356-62.
72. Decuypere JP, Welkenhuyzen K, Luyten T, Ponsaerts R, Dewaele M, Molgo J, et al. Ins(1,4,5)P3 receptor-mediated Ca2+ signaling and autophagy induction are interrelated. Autophagy 2011; 7: 1472-89.
73. Vicencio JM, Ortiz C, Criollo A, Jones AW, Kepp O, Galluzzi L, et al. The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ 2009; 16: 1006-17.
74. Criollo A, Vicencio JM, Tasdemir E, Maiuri MC, Lavandero S, Kroemer G. The inositol trisphosphate receptor in the control of autophagy. Autophagy 2007; 3: 350-3.
75. Hou H, Zhang Y, Huang Y, Yi Q, Lv L, Zhang T, et al. Inhibitors of phosphatidylinositol 3′-kinases promote mitotic cell death in HeLa cells. PLOS ONE 2012; 7: e35665.
76. Castino R, Bellio N, Follo C, Murphy D, Isidoro C. Inhibition of PI3k class III-dependent autophagy prevents apoptosis and necrosis by oxidative stress in dopaminergic neuroblastoma cells. Toxicol Sci 2010; 117: 152-62.
77. Miller S, Tavshanjian B, Oleksy A, Perisic O, Houseman BT, Shokat KM, et al. Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34. Science 2010; 327: 1638-42.
78. Seglen PO, Gordon PB. 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A 1982; 79: 1889-92.
79. Martelli AM, Chiarini F, Evangelisti C, Cappellini A, Buontempo F, Bressanin D, et al. Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget 2012; 3: 371-94.
80. Takatsuka C, Inoue Y, Matsuoka K, Moriyasu Y. 3-methyladenine inhibits autophagy in tobacco culture cells under sucrose starvation conditions. Plant Cell Physiol 2004; 45: 265-74.
81. Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 2010; 285: 10850-61.
82. Bright NA, Lindsay MR, Stewart A, Luzio JP. The relationship between lumenal and limiting membranes in swollen late endocytic compartments formed after wortmannin treatment or sucrose accumulation. Traffic 2001; 2: 631-42.
83. Xing C, Zhu B, Liu H, Yao H, Zhang L. Class I phosphatidylinositol 3-kinase inhibitor LY294002 activates autophagy and induces apoptosis through p53 pathway in gastric cancer cell line SGC7901. Acta Biochim Biophys Sin (Shanghai) 2008; 40: 194-201.
84. Ethier MF, Madison JM. LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells. Cell Calcium 2002; 32: 31-8.
85. Rez G, Kovacs J. Prevention by cycloheximide of cellular autophagy induced by hyperosmotic sucrose or cadmium chloride in mouse pancreatic acinar cells. Acta Biol Acad Sci Hung 1973; 24: 201-5.
86. Kovacs J. Regression of autophagic vacuoles in seminal vesicle cells following cycloheximide treatment. Exp Cell Res 1983; 144: 231-4.
87. Oliva O, Rez G, Palfia Z, Fellinger E. Dynamics of vinblastine-induced autophagocytosis in murine pancreatic acinar cells: influence of cycloheximide post-treatments. Exp Mol Pathol 1992; 56: 76-86.
88. Machiya Y, Hara S, Arawaka S, Fukushima S, Sato H, Sakamoto M, et al. Phosphorylated alpha-synuclein at Ser-129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J Biol Chem 2010; 285: 40732-44.
89. Lawrence BP, Brown WJ. Inhibition of protein synthesis separates autophagic sequestration from the delivery of lysosomal enzymes. J Cell Sci 1993; 105: 473-80.
90. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. 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 1998; 23: 33-42.
91. Wu YC, Wu WK, Li Y, Yu L, Li ZJ, Wong CC, et al. Inhibition of macroautophagy by bafilomycin A1 lowers proliferation and induces apoptosis in colon cancer cells. Biochem Biophys Res Commun 2009; 382: 451-6.
92. Klionsky DJ, Elazar Z, Seglen PO, Rubinsztein DC. Does bafilomycin A1 block the fusion of autophagosomes with lysosomes. Autophagy 2008; 4: 849-950.
93. Chen G, Ke Z, Xu M, Liao M, Wang X, Qi Y, et al. Autophagy is a protective response to ethanol neurotoxicity. Autophagy 2012; 8: 1577-89.
94. Dengjel J, Hoyer-Hansen M, Nielsen MO, Eisenberg T, Harder LM, Schandorff S, et al. Identification of autophagosome-associated proteins and regulators by quantitative proteomic analysis and genetic screens. Mol Cell Proteomics 2012; 11: M111.014035.
95. Harhaji-Trajkovic L, Arsikin K, Kravic-Stevovic T, Petricevic S, Tovilovic G, Pantovic A, et al. Chloroquine-mediated lysosomal dysfunction enhances the anticancer effect of nutrient deprivation. Pharm Res 2012; 29: 2249-63.
96. Amaravadi RK, Winkler JD. Lys05: A new lysosomal autophagy inhibitor. Autophagy 2012; 8: 1383-4.
97. McAfee Q, Zhang Z, Samanta A, Levi SM, Ma XH, Piao S, et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci U S A 2012; 109: 8253-8.
98. Moriyasu Y, Inoue Y. Use of protease inhibitors for detecting autophagy in plants. Methods Enzymol 2008; 451: 557-80.
99. Kominami E, Hashida S, Khairallah EA, Katunuma N. Sequestration of cytoplasmic enzymes in an autophagic vacuole-lysosomal system induced by injection of leupeptin. J Biol Chem 1983; 258: 6093-100.
100. Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 2005; 1: 84-91.
101. Ni HM, Bockus A, Wozniak AL, Jones K, Weinman S, Yin XM, et al. Dissecting the dynamic turnover of GFP-LC3 in the autolysosome. Autophagy 2011; 7: 188-204.
102. Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 1997; 243: 240-6.
103. Christian F, Anthony DF, Vadrevu S, Riddell T, Day JP, McLeod R, et al. p62 (SQSTM1) and cyclic AMP phosphodiesterase-4A4 (PDE4A4) locate to a novel, reversible protein aggregate with links to autophagy and proteasome degradation pathways. Cell Signal 2010; 22: 1576-96.
104. Ramser B, Kokot A, Metze D, Weiss N, Luger TA, Bohm M. Hydroxychloroquine modulates metabolic activity and proliferation and induces autophagic cell death of human dermal fibroblasts. J Invest Dermatol 2009; 129: 2419-26.
105. Oikarinen A. Hydroxychloroquine induces autophagic cell death of human dermal fibroblasts: implications for treating fibrotic skin diseases. J Invest Dermatol 2009; 129: 2333-5.
106. Amaravadi RK, Winkler JD. Lys05: a new lysosomal autophagy inhibitor. Autophagy 2012; 8: 1383-4.
107. Aronson NN Jr, Dennis PA, Dunn WA. Metabolism of leupeptin and its effect on autophagy in the perfused rat liver. Acta Biol Med Ger 1981; 40: 1531-8.
108. Dong XX, Wang YR, Qin S, Liang ZQ, Liu BH, Qin ZH, et al. p53 Mediates autophagy activation and mitochondria dysfunction in kainic acid-induced excitotoxicity in primary striatal neurons. Neuroscience 2012; 207: 52-64.
109. Tanida I. Autophagy basics. Microbiol Immunol 2011; 55: 1-11.
110. Frankel LB, Wen J, Lees M, Hoyer-Hansen M, Farkas T, Krogh A, et al. microRNA-101 is a potent inhibitor of autophagy. EMBO J 2011; 30: 4628-41.
111. Yu Y, Yang L, Zhao M, Zhu S, Kang R, Vernon P, et al. Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells. Leukemia 2012; 26: 1752-60.
112. Yuya N, Satoko A, Kenji F, Hirofumi Y, Takeshi M, Toku K, et al. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 2009; 461: 654-8.
113. Grishchuk Y, Ginet V, Truttmann AC, Clarke PG, Puyal J. Beclin 1-independent autophagy contributes to apoptosis in cortical neurons. Autophagy 2011; 7: 1115-31.
114. Beau I, Mehrpour M, Codogno P. Autophagosomes and human diseases. Int J Biochem Cell Biol 2011; 43: 460-4.
115. Bursch W EA, Gerner C SR. (2004). Autophagocytosis and programmed cell death. In: Klionsky DJ, editor. Autophagy. Georgetown, TX: Landes Bioscience, 2004. p287-303 .
116. Shintani T, Klionsky DJ. Autophagy in health and disease: a doubleedged sword. Science 2004; 306: 990-5.
117. Apel A, Zentgraf H, Buchler MW, Herr I. Autophagy-A double-edged sword in oncology. Int J Cancer 2009; 125: 991-5.
118. Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 2011; 147: 223-34.
119. Zhao Y, Xiong X, Sun Y. DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(betaTrCP) E3 ubiquitin ligase and regulates survival and autophagy. Mol Cell 2011; 44: 304-16.
120. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009; 284: 8023-32.
121. Petrovski G, Gurusamy N, Das DK. Resveratrol in cardiovascular health and disease. Ann N Y Acad Sci 2011; 1215: 22-33.
122. Li CY, Wang EQ, Cheng Y, Bao JK. Oridonin: An active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics. Int J Biochem Cell Biol 2011; 43: 701-4.
123. Cao BY, Yang YP, Luo WF, Mao CJ, Han R, Sun X, et al. Paeoniflorin, a potent natural compound, protects PC12 cells from MPP+ and acidic damage via autophagic pathway. J Ethnopharmacol 2010; 131: 122-9.
124. Yang S, Xiao X, Meng X, Leslie KK. A mechanism for synergy with combined mTOR and PI3 kinase inhibitors. PLOS One 2011; 6: e26343.
125. Sarkar S, Krishna G, Imarisio S, Saiki S, O'Kane CJ, Rubinsztein DC. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet 2008; 17: 170-8.