Advertisement

Bioprobes pp 75-113 | Cite as

Apoptosis and Autophagy

  • Etsu Tashiro
  • Mitsuhiro Kitagawa
  • Masaya Imoto
Chapter

Abstract

Apoptosis and autophagy are highly coordinated mechanisms to maintain cellular homeostasis against various intrinsic and/or extrinsic stresses in eukaryotic cells. Since the early 1990s, our knowledge of the molecular mechanisms and the physiological functions of apoptosis have increased substantially. Dysfunction of apoptosis leads to various diseases, including cancers and degenerative diseases. Therefore, small molecules that induce apoptosis or synthetic lethality with mutated genes have been examined for the development of cancer-specific apoptosis-inducing agents; conversely, small molecules that suppress apoptosis have been identified for protective agents against neuronal cell death.

On the other hand, autophagy is an evolutionarily conserved pathway involved in the degradation of intracellular components and is critical for the maintenance of cellular homeostasis. The mechanisms and functions of autophagy have been revealed by genetic studies in yeast, which identified a series of autophagy-related genes. Many small molecules that have been discovered to induce or inhibit autophagy also provide insight into the mechanisms and functions of the autophagic process. In this chapter, we introduce several small molecules identified by synthetic lethality screening, apoptosis inhibitors, and autophagy modulators.

Keywords

Apoptosis Synthetic lethality Oncogene Cancer Neurodegenerative disease Neuroprotection Autophagy 

References

  1. 1.
    White E (1993) Regulation of apoptosis by the transforming genes of the DNA tumor virus adenovirus. Proc Soc Exp Biol Med 204(1):30–39PubMedCrossRefGoogle Scholar
  2. 2.
    Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M (1991) Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352(6333):345–347. doi: 10.1038/352345a0 PubMedCrossRefGoogle Scholar
  3. 3.
    Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC (1992) Induction of apoptosis in fibroblasts by c-myc protein. Cell 69(1):119–128PubMedCrossRefGoogle Scholar
  4. 4.
    Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S, White E (1992) The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci U S A 89(16):7742–7746PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Wagner AJ, Kokontis JM, Hay N (1994) Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev 8(23):2817–2830PubMedCrossRefGoogle Scholar
  6. 6.
    Lin Y, Benchimol S (1995) Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest. Mol Cell Biol 15(11):6045–6054PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Sakamuro D, Eviner V, Elliott KJ, Showe L, White E, Prendergast GC (1995) c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms. Oncogene 11(11):2411–2418PubMedGoogle Scholar
  8. 8.
    Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362(6423):849–852. doi: 10.1038/362849a0 PubMedCrossRefGoogle Scholar
  9. 9.
    Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362(6423):847–849. doi: 10.1038/362847a0 PubMedCrossRefGoogle Scholar
  10. 10.
    Han Z, Chatterjee D, He DM, Early J, Pantazis P, Wyche JH, Hendrickson EA (1995) Evidence for a G2 checkpoint in p53-independent apoptosis induction by X-irradiation. Mol Cell Biol 15(11):5849–5857PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lowe SW, Ruley HE, Jacks T, Housman DE (1993) p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74(6):957–967PubMedCrossRefGoogle Scholar
  12. 12.
    Shawver LK, Slamon D, Ullrich A (2002) Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell 1(2):117–123PubMedCrossRefGoogle Scholar
  13. 13.
    Capdeville R, Buchdunger E, Zimmermann J, Matter A (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1(7):493–502. doi: 10.1038/nrd839 PubMedCrossRefGoogle Scholar
  14. 14.
    Burris HA 3rd (2004) Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. Oncologist 9(Suppl 3):10–15PubMedCrossRefGoogle Scholar
  15. 15.
    Weinstein IB (2002) Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297(5578):63–64. doi: 10.1126/science.1073096 PubMedCrossRefGoogle Scholar
  16. 16.
    Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW (2011) Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475(7355):231–234. doi: 10.1038/nature10167 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Sung JY, Kim J, Paik SR, Park JH, Ahn YS, Chung KC (2001) Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein. J Biol Chem 276(29):27441–27448. doi: 10.1074/jbc.M101318200 PubMedCrossRefGoogle Scholar
  18. 18.
    Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem 285(12):9262–9272. doi: 10.1074/jbc.M109.081125 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, Meaney DF, Trojanowski JQ, Lee VM (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72(1):57–71. doi: 10.1016/j.neuron.2011.08.033 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6(4):304–312. doi: 10.1038/nrd2272 PubMedCrossRefGoogle Scholar
  21. 21.
    Rubinsztein DC (2002) Lessons from animal models of Huntington's disease. Trends Genet 18(4):202–209PubMedCrossRefGoogle Scholar
  22. 22.
    Mattson MP (2004) Pathways towards and away from Alzheimer's disease. Nature 430(7000):631–639. doi: 10.1038/nature02621 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405(6784):360–364. doi: 10.1038/35012636 PubMedCrossRefGoogle Scholar
  24. 24.
    Spillantini MG, Bird TD, Ghetti B (1998) Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 8(2):387–402PubMedCrossRefGoogle Scholar
  25. 25.
    Ohsumi Y (2001) Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2(3):211–216. doi: 10.1038/35056522 PubMedCrossRefGoogle Scholar
  26. 26.
    Yoshimori T (2004) Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun 313(2):453–458PubMedCrossRefGoogle Scholar
  27. 27.
    Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147(4):728–741. doi: 10.1016/j.cell.2011.10.026 PubMedCrossRefGoogle Scholar
  28. 28.
    Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435(7042):677–681. doi: 10.1038/nature03579 PubMedCrossRefGoogle Scholar
  29. 29.
    Adams R, Geissman TA, Edwards JD (1960) Gossypol, a pigment of cottonseed. Chem Rev 60:555–574PubMedCrossRefGoogle Scholar
  30. 30.
    Kitada S, Leone M, Sareth S, Zhai D, Reed JC, Pellecchia M (2003) Discovery, characterization, and structure–activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J Med Chem 46(20):4259–4264. doi: 10.1021/jm030190z PubMedCrossRefGoogle Scholar
  31. 31.
    Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Belec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC (2007) Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci U S A 104(49):19512–19517. doi: 10.1073/pnas.0709443104 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hughes CC, Prieto-Davo A, Jensen PR, Fenical W (2008) The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp. Org Lett 10(4):629–631. doi: 10.1021/ol702952n PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Doi K, Li R, Sung SS, Wu H, Liu Y, Manieri W, Krishnegowda G, Awwad A, Dewey A, Liu X, Amin S, Cheng C, Qin Y, Schonbrunn E, Daughdrill G, Loughran TP Jr, Sebti S, Wang HG (2012) Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem 287(13):10224–10235. doi: 10.1074/jbc.M111.334532 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Cohen NA, Stewart ML, Gavathiotis E, Tepper JL, Bruekner SR, Koss B, Opferman JT, Walensky LD (2012) A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol 19(9):1175–1186. doi: 10.1016/j.chembiol.2012.07.018 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108(2):153–164PubMedCrossRefGoogle Scholar
  36. 36.
    Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, Tominaga F, Hatakeyama S, Kinoyama I, Matsuhisa A, Kudoh M, Sasamata M (2007) YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 67(17):8014–8021. doi: 10.1158/0008-5472.CAN-07-1343 PubMedCrossRefGoogle Scholar
  37. 37.
    Kawamura T, Matsubara K, Otaka H, Tashiro E, Shindo K, Yanagita RC, Irie K, Imoto M (2011) Generation of 'Unnatural Natural Product' library and identification of a small molecule inhibitor of XIAP. Bioorg Med Chem 19(14):4377–4385. doi: 10.1016/j.bmc.2011.05.009 PubMedCrossRefGoogle Scholar
  38. 38.
    Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87(1):99–163. doi: 10.1152/physrev.00013.2006 PubMedCrossRefGoogle Scholar
  39. 39.
    Machida K, Hayashi Y, Osada H (2002) A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release by a mitochondrial permeability transition-independent mechanism. J Biol Chem 277(34):31243–31248. doi: 10.1074/jbc.M204564200 PubMedCrossRefGoogle Scholar
  40. 40.
    Watabe M, Machida K, Osada H (2000) MT-21 is a synthetic apoptosis inducer that directly induces cytochrome c release from mitochondria. Cancer Res 60(18):5214–5222PubMedGoogle Scholar
  41. 41.
    Marchetti P, Zamzami N, Joseph B, Schraen-Maschke S, Mereau-Richard C, Costantini P, Metivier D, Susin SA, Kroemer G, Formstecher P (1999) The novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid can trigger apoptosis through a mitochondrial pathway independent of the nucleus. Cancer Res 59(24):6257–6266PubMedGoogle Scholar
  42. 42.
    Belzacq AS, El Hamel C, Vieira HL, Cohen I, Haouzi D, Metivier D, Marchetti P, Brenner C, Kroemer G (2001) Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene 20(52):7579–7587. doi: 10.1038/sj.onc.1204953 PubMedCrossRefGoogle Scholar
  43. 43.
    Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH (1997) Integrating genetic approaches into the discovery of anticancer drugs. Science 278(5340):1064–1068PubMedCrossRefGoogle Scholar
  44. 44.
    Guarente L (1993) Synthetic enhancement in gene interaction: a genetic tool come of age. Trends Genet 9(10):362–366PubMedCrossRefGoogle Scholar
  45. 45.
    Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411(6835):366–374. doi: 10.1038/35077232 PubMedCrossRefGoogle Scholar
  46. 46.
    Tutt A, Ashworth A (2002) The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 8(12):571–576PubMedCrossRefGoogle Scholar
  47. 47.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921. doi: 10.1038/nature03445 PubMedCrossRefGoogle Scholar
  48. 48.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917. doi: 10.1038/nature03443 PubMedCrossRefGoogle Scholar
  49. 49.
    Wray GM, Hinds CJ, Thiemermann C (1998) Effects of inhibitors of poly(ADP-ribose) synthetase activity on hypotension and multiple organ dysfunction caused by endotoxin. Shock 10(1):13–19PubMedCrossRefGoogle Scholar
  50. 50.
    Bowman KJ, Newell DR, Calvert AH, Curtin NJ (2001) Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. Br J Cancer 84(1):106–112. doi: 10.1054/bjoc.2000.1555 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Skalitzky DJ, Marakovits JT, Maegley KA, Ekker A, Yu XH, Hostomsky Z, Webber SE, Eastman BW, Almassy R, Li J, Curtin NJ, Newell DR, Calvert AH, Griffin RJ, Golding BT (2003) Tricyclic benzimidazoles as potent poly(ADP-ribose) polymerase-1 inhibitors. J Med Chem 46(2):210–213. doi: 10.1021/jm0255769 PubMedCrossRefGoogle Scholar
  52. 52.
    Wooster R, Weber BL (2003) Breast and ovarian cancer. N Engl J Med 348(23):2339–2347. doi: 10.1056/NEJMra012284 PubMedCrossRefGoogle Scholar
  53. 53.
    Menear KA, Adcock C, Boulter R, Cockcroft XL, Copsey L, Cranston A, Dillon KJ, Drzewiecki J, Garman S, Gomez S, Javaid H, Kerrigan F, Knights C, Lau A, Loh VM Jr, Matthews IT, Moore S, O'Connor MJ, Smith GC, Martin NM (2008) 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 51(20):6581–6591. doi: 10.1021/jm8001263 PubMedCrossRefGoogle Scholar
  54. 54.
    Torrance CJ, Agrawal V, Vogelstein B, Kinzler KW (2001) Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nat Biotechnol 19(10):940–945. doi: 10.1038/nbt1001-940 PubMedCrossRefGoogle Scholar
  55. 55.
    Dolma S, Lessnick SL, Hahn WC, Stockwell BR (2003) Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3(3):285–296PubMedCrossRefGoogle Scholar
  56. 56.
    Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR (2007) RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447(7146):864–868. doi: 10.1038/nature05859 PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Guo W, Wu S, Liu J, Fang B (2008) Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota. Cancer Res 68(18):7403–7408. doi: 10.1158/0008-5472.CAN-08-1449 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Shaw AT, Winslow MM, Magendantz M, Ouyang C, Dowdle J, Subramanian A, Lewis TA, Maglathin RL, Tolliday N, Jacks T (2011) Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci U S A 108(21):8773–8778. doi: 10.1073/pnas.1105941108 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Furuta Y, Yoshikawa A (1976) Reversible adrenergic alpha-receptor blocking action of 2,4′-dimethyl-3-piperidino-propiophenone (tolperisone). Jpn J Pharmacol 26(5):543–550PubMedCrossRefGoogle Scholar
  60. 60.
    Sakitama K, Ozawa Y, Aoto N, Tomita H, Ishikawa M (1997) Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes. Eur J Pharmacol 337(2-3):175–187PubMedCrossRefGoogle Scholar
  61. 61.
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102(43):15545–15550. doi: 10.1073/pnas.0506580102 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313(5795):1929–1935. doi: 10.1126/science.1132939 PubMedCrossRefGoogle Scholar
  63. 63.
    Lane HA, Beuvink I, Motoyama AB, Daly JM, Neve RM, Hynes NE (2000) ErbB2 potentiates breast tumor proliferation through modulation of p27(Kip1)-Cdk2 complex formation: receptor overexpression does not determine growth dependency. Mol Cell Biol 20(9):3210–3223PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Neve RM, Lane HA, Hynes NE (2001) The role of overexpressed HER2 in transformation. Ann Oncol 12(Suppl 1):S9–13PubMedCrossRefGoogle Scholar
  65. 65.
    Fantin VR, Berardi MJ, Scorrano L, Korsmeyer SJ, Leder P (2002) A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. Cancer Cell 2(1):29–42PubMedCrossRefGoogle Scholar
  66. 66.
    Bateman RL, Rauh D, Tavshanjian B, Shokat KM (2008) Human carbonyl reductase 1 is an S-nitrosoglutathione reductase. J Biol Chem 283(51):35756–35762. doi: 10.1074/jbc.M807125200 PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ralat LA, Manevich Y, Fisher AB, Colman RF (2006) Direct evidence for the formation of a complex between 1-cysteine peroxiredoxin and glutathione S-transferase pi with activity changes in both enzymes. Biochemistry 45(2):360–372. doi: 10.1021/bi0520737 PubMedCrossRefGoogle Scholar
  68. 68.
    Li R, Murray AW (1991) Feedback control of mitosis in budding yeast. Cell 66(3):519–531PubMedCrossRefGoogle Scholar
  69. 69.
    Sotillo R, Schvartzman JM, Socci ND, Benezra R (2010) Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464(7287):436–440. doi: 10.1038/nature08803 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Bian Y, Kitagawa R, Bansal PK, Fujii Y, Stepanov A, Kitagawa K (2014) Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1315588111 Google Scholar
  71. 71.
    Tarleton M, Gilbert J, Sakoff JA, McCluskey A (2012) Synthesis and anticancer activity of a series of norcantharidin analogues. Eur J Med Chem 54:573–581. doi: 10.1016/j.ejmech.2012.06.010 PubMedCrossRefGoogle Scholar
  72. 72.
    Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, Riisnaes R, Pope LL, Heaton SP, Thomas G, Garrett MD, Sullivan DM, de Bono JS, Tolcher AW (2011) First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29(35):4688–4695. doi: 10.1200/JCO.2011.35.5263 PubMedCrossRefGoogle Scholar
  73. 73.
    Dai B, Yoo SY, Bartholomeusz G, Graham RA, Majidi M, Yan S, Meng J, Ji L, Coombes K, Minna JD, Fang B, Roth JA (2013) KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer. Cancer Res 73(17):5532–5543. doi: 10.1158/0008-5472.CAN-13-0712 PubMedCrossRefGoogle Scholar
  74. 74.
    Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, Reynolds GE, Chi JT, Wu J, Solow-Cordero DE, Bonnet M, Flanagan JU, Bouley DM, Graves EE, Denny WA, Hay MP, Giaccia AJ (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3(94):94ra70. doi: 10.1126/scitranslmed.3002394 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    DeBoer C, Meulman PA, Wnuk RJ, Peterson DH (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo) 23(9):442–447CrossRefGoogle Scholar
  76. 76.
    Sasaki K, Rinehart KL Jr, Slomp G, Grostic MF, Olson EC (1970) Geldanamycin I structure assignment. J Am Chem Soc 92(26):7591–7593PubMedCrossRefGoogle Scholar
  77. 77.
    Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91(18):8324–8328PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Gallo KA (2006) Targeting HSP90 to halt neurodegeneration. Chem Biol 13(2):115–116. doi: 10.1016/j.chembiol.2006.02.003 PubMedCrossRefGoogle Scholar
  79. 79.
    Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8(11):1185–1186. doi: 10.1038/nm1102-1185 PubMedCrossRefGoogle Scholar
  80. 80.
    McLean PJ, Klucken J, Shin Y, Hyman BT (2004) Geldanamycin induces Hsp70 and prevents alpha-synuclein aggregation and toxicity in vitro. Biochem Biophys Res Commun 321(3):665–669. doi: 10.1016/j.bbrc.2004.07.021 PubMedCrossRefGoogle Scholar
  81. 81.
    Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M (2004) CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet 13(7):703–714. doi: 10.1093/hmg/ddh083 PubMedCrossRefGoogle Scholar
  82. 82.
    Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Sobue G (2006) Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG). Ann N Y Acad Sci 1086:21–34. doi: 10.1196/annals.1377.012 PubMedCrossRefGoogle Scholar
  83. 83.
    Cysyk RL, Parker RJ, Barchi JJ Jr, Steeg PS, Hartman NR, Strong JM (2006) Reaction of geldanamycin and C17-substituted analogues with glutathione: product identifications and pharmacological implications. Chem Res Toxicol 19(3):376–381. doi: 10.1021/tx050237e PubMedCrossRefGoogle Scholar
  84. 84.
    Kitson RR, Chang CH, Xiong R, Williams HE, Davis AL, Lewis W, Dehn DL, Siegel D, Roe SM, Prodromou C, Ross D, Moody CJ (2013) Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90. Nat Chem 5(4):307–314. doi: 10.1038/nchem.1596 PubMedCrossRefGoogle Scholar
  85. 85.
    Feany MB, Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404(6776):394–398. doi: 10.1038/35006074 PubMedCrossRefGoogle Scholar
  86. 86.
    Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295(5556):865–868. doi: 10.1126/science.1067389 PubMedCrossRefGoogle Scholar
  87. 87.
    Patury S, Miyata Y, Gestwicki JE (2009) Pharmacological targeting of the Hsp70 chaperone. Curr Top Med Chem 9(15):1337–1351PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sassa H, Takaishi Y, Terada H (1990) The triterpene celastrol as a very potent inhibitor of lipid peroxidation in mitochondria. Biochem Biophys Res Commun 172(2):890–897PubMedCrossRefGoogle Scholar
  89. 89.
    Westerheide SD, Bosman JD, Mbadugha BN, Kawahara TL, Matsumoto G, Kim S, Gu W, Devlin JP, Silverman RB, Morimoto RI (2004) Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 279(53):56053–56060. doi: 10.1074/jbc.M409267200 PubMedCrossRefGoogle Scholar
  90. 90.
    Murakami M, Oketani K, Fujisaki H, Wakabayashi T, Ohgo T (1981) Antiulcer effect of geranylgeranylacetone, a new acyclic polyisoprenoid on experimentally induced gastric and duodenal ulcers in rats. Arzneimittelforschung 31(5):799–804PubMedGoogle Scholar
  91. 91.
    Pinder RM, Brogden RN, Sawyer PR, Speight TM, Spencer R, Avery GS (1976) Carbenoxolone: a review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease. Drugs 11(4):245–307PubMedCrossRefGoogle Scholar
  92. 92.
    Yamanaka K, Takahashi N, Ooie T, Kaneda K, Yoshimatsu H, Saikawa T (2003) Role of protein kinase C in geranylgeranylacetone-induced expression of heat-shock protein 72 and cardioprotection in the rat heart. J Mol Cell Cardiol 35(7):785–794PubMedCrossRefGoogle Scholar
  93. 93.
    Nagayama S, Jono H, Suzaki H, Sakai K, Tsuruya E, Yamatsu I, Isohama Y, Miyata T, Kai H (2001) Carbenoxolone, a new inducer of heat shock protein 70. Life Sci 69(24):2867–2873PubMedCrossRefGoogle Scholar
  94. 94.
    Deng YN, Shi J, Liu J, Qu QM (2013) Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int 63(1):1–9. doi: 10.1016/j.neuint.2013.04.005 PubMedCrossRefGoogle Scholar
  95. 95.
    Kilpatrick K, Novoa JA, Hancock T, Guerriero CJ, Wipf P, Brodsky JL, Segatori L (2013) Chemical induction of Hsp70 reduces alpha-synuclein aggregation in neuroglioma cells. ACS Chem Biol 8(7):1460–1468. doi: 10.1021/cb400017h PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Aronson AL (1980) Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Assoc 176(10 Spec No):1061-1068Google Scholar
  97. 97.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7):797–801. doi: 10.1038/77528 PubMedCrossRefGoogle Scholar
  98. 98.
    Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH (2007) Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology 32(11):2393–2404. doi: 10.1038/sj.npp.1301377 PubMedCrossRefGoogle Scholar
  99. 99.
    Sancho M, Herrera AE, Gortat A, Carbajo RJ, Pineda-Lucena A, Orzaez M, Perez-Paya E (2011) Minocycline inhibits cell death and decreases mutant Huntingtin aggregation by targeting Apaf-1. Hum Mol Genet 20(18):3545–3553. doi: 10.1093/hmg/ddr271 PubMedCrossRefGoogle Scholar
  100. 100.
    Moresco EM, Koleske AJ (2003) Regulation of neuronal morphogenesis and synaptic function by Abl family kinases. Curr Opin Neurobiol 13(5):535–544PubMedCrossRefGoogle Scholar
  101. 101.
    Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM (2010) Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc Natl Acad Sci U S A 107(38):16691–16696. doi: 10.1073/pnas.1006083107 PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Alvarez AR, Sandoval PC, Leal NR, Castro PU, Kosik KS (2004) Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species. Neurobiol Dis 17(2):326–336. doi: 10.1016/j.nbd.2004.06.007 PubMedCrossRefGoogle Scholar
  103. 103.
    Alvarez AR, Klein A, Castro J, Cancino GI, Amigo J, Mosqueira M, Vargas LM, Yevenes LF, Bronfman FC, Zanlungo S (2008) Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann–Pick type C disease. FASEB J 22(10):3617–3627. doi: 10.1096/fj.07-102715 PubMedCrossRefGoogle Scholar
  104. 104.
    Wolff NC, Richardson JA, Egorin M, Ilaria RL Jr (2003) The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood 101(12):5010–5013. doi: 10.1182/blood-2002-10-3059 PubMedCrossRefGoogle Scholar
  105. 105.
    Hebron ML, Lonskaya I, Moussa CE (2013) Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. Hum Mol Genet 22(16):3315–3328. doi: 10.1093/hmg/ddt192 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Otomo M, Takahashi K, Miyoshi H, Osada K, Nakashima H, Yamaguchi N (2008) Some selective serotonin reuptake inhibitors inhibit dynamin I guanosine triphosphatase (GTPase). Biol Pharm Bull 31(8):1489–1495PubMedCrossRefGoogle Scholar
  107. 107.
    Takahashi K, Miyoshi H, Otomo M, Osada K, Yamaguchi N, Nakashima H (2010) Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis. Biochem Biophys Res Commun 391(1):382–387. doi: 10.1016/j.bbrc.2009.11.067 PubMedCrossRefGoogle Scholar
  108. 108.
    Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ (2008) Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int J Biochem Cell Biol 40(9):1835–1849. doi: 10.1016/j.biocel.2008.01.017 PubMedCrossRefGoogle Scholar
  109. 109.
    Lee SJ (2008) Origins and effects of extracellular alpha-synuclein: implications in Parkinson's disease. J Mol Neurosci 34(1):17–22. doi: 10.1007/s12031-007-0012-9 PubMedCrossRefGoogle Scholar
  110. 110.
    Zhang J, Ferguson SS, Barak LS, Menard L, Caron MG (1996) Dynamin and beta-arrestin reveal distinct mechanisms for G protein-coupled receptor internalization. J Biol Chem 271(31):18302–18305PubMedCrossRefGoogle Scholar
  111. 111.
    Konno M, Hasegawa T, Baba T, Miura E, Sugeno N, Kikuchi A, Fiesel FC, Sasaki T, Aoki M, Itoyama Y, Takeda A (2012) Suppression of dynamin GTPase decreases alpha-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy. Mol Neurodegener 7:38. doi: 10.1186/1750-1326-7-38 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5(4):539–545PubMedCrossRefGoogle Scholar
  113. 113.
    Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273(7):3963–3966PubMedCrossRefGoogle Scholar
  114. 114.
    Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ (1995) Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270(5):2320–2326PubMedCrossRefGoogle Scholar
  115. 115.
    Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175PubMedCrossRefGoogle Scholar
  116. 116.
    Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, Amano A, Yoshimori T (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495(7441):389–393. doi: 10.1038/nature11910 PubMedCrossRefGoogle Scholar
  117. 117.
    Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023–8032. doi: 10.1074/jbc.M900301200 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Balgi AD, Fonseca BD, Donohue E, Tsang TC, Lajoie P, Proud CG, Nabi IR, Roberge M (2009) Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling. PLoS One 4(9):e7124. doi: 10.1371/journal.pone.0007124 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJ, Wan NC, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ (2008) The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 51(18):5522–5532. doi: 10.1021/jm800295d PubMedCrossRefGoogle Scholar
  120. 120.
    Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T (2006) Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 98(8):545–556. doi: 10.1093/jnci/djj133 PubMedCrossRefGoogle Scholar
  121. 121.
    Kong D, Dan S, Yamazaki K, Yamori T (2010) Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39. Eur J Cancer 46(6):1111–1121. doi: 10.1016/j.ejca.2010.01.005 PubMedCrossRefGoogle Scholar
  122. 122.
    Wang Y, Liu J, Qiu Y, Jin M, Chen X, Fan G, Wang R, Kong D (2016) ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells. Oncotarget 7(15):19897–19909. doi: 10.18632/oncotarget.7658 PubMedPubMedCentralGoogle Scholar
  123. 123.
    Blommaart EF, Krause U, Schellens JP, Vreeling-Sindelarova H, Meijer AJ (1997) The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243(1-2):240–246PubMedCrossRefGoogle Scholar
  124. 124.
    Seglen PO, Gordon PB (1982) 3-Methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc Natl Acad Sci U S A 79(6):1889–1892PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Liu J, Xia H, Kim M, Xu L, Li Y, Zhang L, Cai Y, Norberg HV, Zhang T, Furuya T, Jin M, Zhu Z, Wang H, Yu J, Hao Y, Choi A, Ke H, Ma D, Yuan J (2011) Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147(1):223–234. doi: 10.1016/j.cell.2011.08.037 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    MacPherson JD, Gillespie TD, Dunkerley HA, Maurice DH, Bennett BM (2006) Inhibition of phosphodiesterase 5 selectively reverses nitrate tolerance in the venous circulation. J Pharmacol Exp Ther 317(1):188–195. doi: 10.1124/jpet.105.094763 PubMedCrossRefGoogle Scholar
  127. 127.
    Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8(10):774–785. doi: 10.1038/nrm2249 PubMedCrossRefGoogle Scholar
  128. 128.
    Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. doi: 10.1038/ncb2152 PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Fryer LG, Parbu-Patel A, Carling D (2002) The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277(28):25226–25232. doi: 10.1074/jbc.M202489200 PubMedCrossRefGoogle Scholar
  130. 130.
    Hawley SA, Gadalla AE, Olsen GS, Hardie DG (2002) The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51(8):2420–2425PubMedCrossRefGoogle Scholar
  131. 131.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174. doi: 10.1172/JCI13505 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67(14):6745–6752. doi: 10.1158/0008-5472.CAN-06-4447 PubMedCrossRefGoogle Scholar
  133. 133.
    Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon JE, Janle EM, Lobo J, Ferruzzi MG, Davies P, Marambaud P (2010) AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem 285(12):9100–9113. doi: 10.1074/jbc.M109.060061 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Luchsinger JA, Mayeux R (2004) Dietary factors and Alzheimer's disease. Lancet Neurol 3(10):579–587. doi: 10.1016/S1474-4422(04)00878-6 PubMedCrossRefGoogle Scholar
  135. 135.
    Carmichael J, Sugars KL, Bao YP, Rubinsztein DC (2002) Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J Biol Chem 277(37):33791–33798. doi: 10.1074/jbc.M204861200 PubMedCrossRefGoogle Scholar
  136. 136.
    Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, Pasco M, Cook LJ, Rubinsztein DC (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170(7):1101–1111. doi: 10.1083/jcb.200504035 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Coyle JT, Duman RS (2003) Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38(2):157–160PubMedCrossRefGoogle Scholar
  138. 138.
    Gould TD, Chen G, Manji HK (2002) Mood stabilizer psychopharmacology. Clin Neurosci Res 2(3-4):193–212. doi: 10.1016/S1566-2772(02)00044-0 PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Atack JR, Cook SM, Watt AP, Fletcher SR, Ragan CI (1993) In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330. J Neurochem 60(2):652–658PubMedCrossRefGoogle Scholar
  140. 140.
    Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7(10):793–803PubMedCrossRefGoogle Scholar
  141. 141.
    Williams RS, Cheng L, Mudge AW, Harwood AJ (2002) A common mechanism of action for three mood-stabilizing drugs. Nature 417(6886):292–295. doi: 10.1038/417292a PubMedCrossRefGoogle Scholar
  142. 142.
    Williams A, Sarkar S, Cuddon P, Ttofi EK, Saiki S, Siddiqi FH, Jahreiss L, Fleming A, Pask D, Goldsmith P, O'Kane CJ, Floto RA, Rubinsztein DC (2008) Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol 4(5):295–305. doi: 10.1038/nchembio.79 PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Quirion JC, Sevenet T, Husson HP, Weniger B, Debitus C (1992) Two new alkaloids from Xestospongia sp., a New Caledonian sponge. J Nat Prod 55(10):1505–1508PubMedCrossRefGoogle Scholar
  144. 144.
    Sato-Kusubata K, Yajima Y, Kawashima S (2000) Persistent activation of Gs alpha through limited proteolysis by calpain. Biochem J 347(Pt 3):733–740PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU (2006) Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 8(10):1124–1132. doi: 10.1038/ncb1482 PubMedCrossRefGoogle Scholar
  146. 146.
    Gafni J, Munsch JA, Lam TH, Catlin MC, Costa LG, Molinski TF, Pessah IN (1997) Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor. Neuron 19(3):723–733PubMedCrossRefGoogle Scholar
  147. 147.
    Criollo A, Vicencio JM, Tasdemir E, Maiuri MC, Lavandero S, Kroemer G (2007) The inositol trisphosphate receptor in the control of autophagy. Autophagy 3(4):350–353PubMedCrossRefGoogle Scholar
  148. 148.
    Vicencio JM, Ortiz C, Criollo A, Jones AW, Kepp O, Galluzzi L, Joza N, Vitale I, Morselli E, Tailler M, Castedo M, Maiuri MC, Molgo J, Szabadkai G, Lavandero S, Kroemer G (2009) The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1. Cell Death Differ 16(7):1006–1017. doi: 10.1038/cdd.2009.34 PubMedCrossRefGoogle Scholar
  149. 149.
    Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72(11):8586–8596PubMedPubMedCentralGoogle Scholar
  150. 150.
    Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402(6762):672–676. doi: 10.1038/45257 PubMedCrossRefGoogle Scholar
  151. 151.
    He C, Levine B (2010) The Beclin 1 interactome. Curr Opin Cell Biol 22(2):140–149. doi: 10.1016/j.ceb.2010.01.001 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Huang S, Sinicrope FA (2010) Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy 6(2):256–269PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Voss V, Senft C, Lang V, Ronellenfitsch MW, Steinbach JP, Seifert V, Kogel D (2010) The pan-Bcl-2 inhibitor (−)-gossypol triggers autophagic cell death in malignant glioma. Mol Cancer Res 8(7):1002–1016. doi: 10.1158/1541-7786.MCR-09-0562 PubMedCrossRefGoogle Scholar
  154. 154.
    McCoy F, Hurwitz J, McTavish N, Paul I, Barnes C, O'Hagan B, Odrzywol K, Murray J, Longley D, McKerr G, Fennell DA (2010) Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK. Cell Death Dis 1:e108. doi: 10.1038/cddis.2010.86 PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Xia HG, Zhang L, Chen G, Zhang T, Liu J, Jin M, Ma X, Ma D, Yuan J (2010) Control of basal autophagy by calpain1 mediated cleavage of ATG5. Autophagy 6(1):61–66PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Djavaheri-Mergny M, Maiuri MC, Kroemer G (2010) Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 29(12):1717–1719. doi: 10.1038/onc.2009.519 PubMedCrossRefGoogle Scholar
  157. 157.
    Luo S, Rubinsztein DC (2010) Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ 17(2):268–277. doi: 10.1038/cdd.2009.121 PubMedCrossRefGoogle Scholar
  158. 158.
    Kaminskyy V, Zhivotovsky B (2012) Proteases in autophagy. Biochim Biophys Acta 1824(1):44–50. doi: 10.1016/j.bbapap.2011.05.013 PubMedCrossRefGoogle Scholar
  159. 159.
    Werner G, Hagenmaier H, Drautz H, Baumgartner A, Zahner H (1984) Metabolic products of microorganisms. 224. Bafilomycins, a new group of macrolide antibiotics. Production, isolation, chemical structure and biological activity. J Antibiot (Tokyo) 37(2):110–117CrossRefGoogle Scholar
  160. 160.
    Bowman EJ, Siebers A, Altendorf K (1988) Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc Natl Acad Sci U S A 85(21):7972–7976PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Hanada H, Moriyama Y, Maeda M, Futai M (1990) Kinetic studies of chromaffin granule H+-ATPase and effects of bafilomycin A1. Biochem Biophys Res Commun 170(2):873–878PubMedCrossRefGoogle Scholar
  162. 162.
    Mellman I, Fuchs R, Helenius A (1986) Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 55:663–700. doi: 10.1146/annurev.bi.55.070186.003311 PubMedCrossRefGoogle Scholar
  163. 163.
    Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y (1992) Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119(2):301–311PubMedCrossRefGoogle Scholar
  164. 164.
    Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, 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(1):33–42PubMedCrossRefGoogle Scholar
  165. 165.
    Suzuki T, Nakagawa M, Yoshikawa A, Sasagawa N, Yoshimori T, Ohsumi Y, Nishino I, Ishiura S, Nonaka I (2002) The first molecular evidence that autophagy relates rimmed vacuole formation in chloroquine myopathy. J Biochem 131(5):647–651PubMedCrossRefGoogle Scholar
  166. 166.
    Brodsky JL, McCracken AA (1999) ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol 10(5):507–513. doi: 10.1006/scdb.1999.0321 PubMedCrossRefGoogle Scholar
  167. 167.
    Kopito RR (1997) ER quality control: the cytoplasmic connection. Cell 88(4):427–430PubMedCrossRefGoogle Scholar
  168. 168.
    Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM (2007) Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171(2):513–524. doi: 10.2353/ajpath.2007.070188 PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447(7146):859–863. doi: 10.1038/nature05853 PubMedCrossRefGoogle Scholar
  170. 170.
    Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS, Pandey UB, Kaushik S, Tresse E, Lu J, Taylor JP, Cuervo AM, Yao TP (2010) HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J 29(5):969–980. doi: 10.1038/emboj.2009.405 PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Ye Y, Meyer HH, Rapoport TA (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414(6864):652–656. doi: 10.1038/414652a PubMedCrossRefGoogle Scholar
  172. 172.
    Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf DH, Sommer T (2002) Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol 4(2):134–139. doi: 10.1038/ncb746 PubMedCrossRefGoogle Scholar
  173. 173.
    Mouysset J, Deichsel A, Moser S, Hoege C, Hyman AA, Gartner A, Hoppe T (2008) Cell cycle progression requires the CDC-48UFD-1/NPL-4 complex for efficient DNA replication. Proc Natl Acad Sci U S A 105(35):12879–12884. doi: 10.1073/pnas.0805944105 PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Partridge JJ, Lopreiato JO Jr, Latterich M, Indig FE (2003) DNA damage modulates nucleolar interaction of the Werner protein with the AAA ATPase p97/VCP. Mol Biol Cell 14(10):4221–4229. doi: 10.1091/mbc.E03-02-0111 PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, Baloh RH, Weihl CC (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187(6):875–888. doi: 10.1083/jcb.200908115 PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Tresse E, Salomons FA, Vesa J, Bott LC, Kimonis V, Yao TP, Dantuma NP, Taylor JP (2010) VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. Autophagy 6(2):217–227PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Rouiller I, DeLaBarre B, May AP, Weis WI, Brunger AT, Milligan RA, Wilson-Kubalek EM (2002) Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle. Nat Struct Biol 9(12):950–957. doi: 10.1038/nsb872 PubMedCrossRefGoogle Scholar
  178. 178.
    DeLaBarre B, Brunger AT (2003) Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat Struct Biol 10(10):856–863. doi: 10.1038/nsb972 PubMedCrossRefGoogle Scholar
  179. 179.
    Sasazawa Y, Kanagaki S, Tashiro E, Nogawa T, Muroi M, Kondoh Y, Osada H, Imoto M (2012) Xanthohumol impairs autophagosome maturation through direct inhibition of valosin-containing protein. ACS Chem Biol 7(5):892–900. doi: 10.1021/cb200492h PubMedCrossRefGoogle Scholar
  180. 180.
    Wang Q, Shinkre BA, Lee JG, Weniger MA, Liu Y, Chen W, Wiestner A, Trenkle WC, Ye Y (2010) The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group. PLoS One 5(11):e15479. doi: 10.1371/journal.pone.0015479 PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Chou TF, Brown SJ, Minond D, Nordin BE, Li K, Jones AC, Chase P, Porubsky PR, Stoltz BM, Schoenen FJ, Patricelli MP, Hodder P, Rosen H, Deshaies RJ (2011) Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways. Proc Natl Acad Sci U S A 108(12):4834–4839. doi: 10.1073/pnas.1015312108 PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Magnaghi P, D'Alessio R, Valsasina B, Avanzi N, Rizzi S, Asa D, Gasparri F, Cozzi L, Cucchi U, Orrenius C, Polucci P, Ballinari D, Perrera C, Leone A, Cervi G, Casale E, Xiao Y, Wong C, Anderson DJ, Galvani A, Donati D, O'Brien T, Jackson PK, Isacchi A (2013) Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death. Nat Chem Biol 9(9):548–556. doi: 10.1038/nchembio.1313 PubMedCrossRefGoogle Scholar
  183. 183.
    Langston JW, Forno LS, Rebert CS, Irwin I (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey. Brain Res 292(2):390–394PubMedCrossRefGoogle Scholar
  184. 184.
    Mizuno Y, Saitoh T, Sone N (1987) Inhibition of mitochondrial alpha-ketoglutarate dehydrogenase by 1-methyl-4-phenylpyridinium ion. Biochem Biophys Res Commun 143(3):971–976PubMedCrossRefGoogle Scholar
  185. 185.
    Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, Kimura M, Komatsu M, Hattori N, Tanaka K (2010) PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 189(2):211–221. doi: 10.1083/jcb.200910140 PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191(7):1367–1380. doi: 10.1083/jcb.201007013 PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Allen GF, Toth R, James J, Ganley IG (2013) Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep 14(12):1127–1135. doi: 10.1038/embor.2013.168 PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Gerlach M, Ben-Shachar D, Riederer P, Youdim MB (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 63(3):793–807PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan KK 2017

Authors and Affiliations

  • Etsu Tashiro
    • 1
  • Mitsuhiro Kitagawa
    • 1
  • Masaya Imoto
    • 1
  1. 1.Department of Biosciences and Informatics, Faculty of Science and TechnologyKeio UniversityYokohamaJapan

Personalised recommendations