Skip to main content
SpringerLink
Log in

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO control on death/life processes in a standardized glioblastoma cell setting. After 90 min irDE-MPIGA cell treatment, 25 nM ligand concentration saturated irreversibly all TSPO binding sites; after 24 h, TSPO de-novo synthesis occurred and about 40 % TSPO binding sites resulted covalently bound to irDE-MPIGA. During cell culture treatments, several dynamic events were observed: (a) early apoptotic markers appeared, such as mitochondrial membrane potential collapse (at 3 h) and externalization of phosphatidylserine (at 6 h); (b) cell viability was reduced (at 6 h), without cell cycle arrest. After digitonin-permeabilized cell suspension treatment, a modulation of mitochondrial permeability transition pore was evidenced. Similar effects were elicited by the reversible TSPO ligand PIGA only when applied at micromolar dose. Interestingly, after 6 h, irDE-MPIGA cell exposure restored cell survival parameters. These results highlighted the ligand-target residence time and the cellular setting are crucial parameters that should be taken into account to understand the drug binding affinity and efficacy correlation and, above all, to translate efficiently cellular drug responses from bench to bedside.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Batarseh A, Papadopoulos V (2010) Regulation of translocator protein 18 kDa (TSPO) expression in health and diseases states. Mol Cell Endocrinol 327:1–12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Costa B, Da Pozzo E, Martini C (2012) Translocator protein as a promising target for novel anxiolytics. Curr Top Med Chem 12:270–285

    Article  CAS  PubMed  Google Scholar 

  3. Taliani S, Da Settimo F, Da Pozzo E, Chelli B, Martini C (2009) Translocator protein ligands as promising therapeutic tools for anxiety disorders. Curr Med Chem 16:3359–3380

    Article  CAS  PubMed  Google Scholar 

  4. Barron AM, Garcia-Segura LM, Caruso D et al (2013) Ligand for translocator protein reverses pathology in a mouse model of Alzheimer’s disease. J Neurosci 33:8891–8897

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Daugherty DJ, Selvaraj V, Chechneva OV, Liu XB, Pleasure DE, Deng W (2013) A TSPO ligand is protective in a mouse model of multiple sclerosis. EMBO Mol Med 5:891–903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Papadopoulos V, Lecanu L (2009) Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma. Exp Neurol 219:53–57

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Girard C, Liu S, Adams D et al (2012) Axonal regeneration and neuroinflammation: roles for the translocator protein 18 kDa. Neuroendocrinol 24:71–81

    Article  CAS  Google Scholar 

  8. Rupprecht R, Papadopoulos V, Rammes G et al (2010) Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov 9:971–988

    Article  CAS  PubMed  Google Scholar 

  9. Qi X, Xu J, Wang F, Xiao J (2012) Translocator protein (18 kDa): a promising therapeutic target and diagnostic tool for cardiovascular diseases. Oxid Med Cell Longev 2012:162934

    PubMed Central  PubMed  Google Scholar 

  10. Caballero B, Veenman L, Gavish M (2013) Role of mitochondrial translocator protein (18 kDa) on mitochondrial-related cell death processes. Recent Pat Endocr Metab Immune Drug Discov 7:86–101

    Article  CAS  PubMed  Google Scholar 

  11. Ikezaki K, Black KL (1990) Stimulation of cell growth and DNA synthesis by peripheral benzodiazepine. Cancer Lett 49:115–120

    Article  CAS  PubMed  Google Scholar 

  12. Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V (1999) Peripheral-type benzodiazepine receptor in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Res 59:831–842

    CAS  PubMed  Google Scholar 

  13. Akech J, Sinha Roy S, Das SK (2005) Modulation of cholinephosphotransferase activity in breast cancer cell lines by Ro5-4864, a peripheral benzodiazepine receptor agonist. Biochem Biophys Res Commun 333:35–41

    Article  CAS  PubMed  Google Scholar 

  14. Bono F, Lamarche I, Prabonnaud V, Le Fur G, Herbert JM (1999) Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities. Biochem Biophys Res Commun 265:457–461

    Article  CAS  PubMed  Google Scholar 

  15. Strohmeier R, Roller M, Sänger N, Knecht R, Kuhl H (2002) Modulation of tamoxifen-induced apoptosis by peripheral benzodiazepine receptor ligands in breast cancer cells. Biochem Pharmacol 64:99–107

    Article  CAS  PubMed  Google Scholar 

  16. Leducq N, Bono F, Sulpice T et al (2003) Role of peripheral benzodiazepine receptors in mitochondrial, cellular, and cardiac damage induced by oxidative stress and ischemia-reperfusion. J Pharmacol Exp Ther 306:828–837

    Article  PubMed  Google Scholar 

  17. Okaro AC, Fennell DA, Corbo M, Davidson BR, Cotter FE (2002) PK11195, a mitochondrial benzodiazepine receptor antagonist, reduces apoptosis threshold in Bcl-XL and Mcl-1 expressing human cholangiocarcinoma cells. Gut 51:556–561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Decaudin D, Castedo M, Nemati F et al (2002) Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo. Cancer Res 62:1388–1393

    CAS  PubMed  Google Scholar 

  19. Xia W, Spector S, Hardy L et al (2000) Tumor selective G2/M cell cycle arrest and apoptosis of epithelial and hematological malignancies by BBL22, a benzazepine. PNAS 97:7494–7499

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Maaser K, Höpfner M, Jansen A et al (2001) Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells. Br J Cancer 85:1771–1780

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Sutter AP, Maaser K, Höpfner M et al (2002) Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human esophageal cancer cells. Int J Cancer 102:318–327

    Article  CAS  PubMed  Google Scholar 

  22. Sutter AP, Maaser K, Barthel B, Scherübl H (2003) Ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in oesophageal cancer cells: involvement of the p38MAPK signalling pathway. Br J Cancer 89:564–572

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Walter RB, Raden BW, Cronk MR, Bernstein ID, Appelbaum FR, Banker DE (2004) The peripheral benzodiazepine receptor ligand PK11195 overcomes different resistance mechanisms to sensitize AML cells to gemtuzumab ozogamicin. Blood 103:4276–4284

    Article  CAS  PubMed  Google Scholar 

  24. Chelli B, Lena A, Vanacore R et al (2004) Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential depolarization and apoptosis induction in rat C6 glioma cells. Biochem Pharmacol 68:125–134

    Article  CAS  PubMed  Google Scholar 

  25. Chelli B, Rossi L, Da Pozzo E et al (2005) PIGA (N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide), a new mitochondrial benzodiazepine-receptor ligand, induces apoptosis in C6 glioma cells. ChemBioChem 6:1082–1088

    Article  CAS  PubMed  Google Scholar 

  26. Park SY, Cho N, Chang I et al (2005) Effect of PK11195, a peripheral benzodiazepine receptor agonist, on insulinoma cell death and insulin secretion. Apoptosis 10:537–544

    Article  CAS  PubMed  Google Scholar 

  27. Jordà EG, Jiménez A, Verdaguer E et al (2005) Evidence in favour of a role for peripheral-type benzodiazepine receptor ligands in amplification of neuronal apoptosis. Apoptosis 10:91–104

    Article  PubMed  Google Scholar 

  28. Shoukrun R, Veenman L, Shandalov Y et al (2008) The 18-kDa translocator protein, formerly known as the peripheral-type benzodiazepine receptor, confers proapoptotic and antineoplastic effects in a human colorectal cancer cell line. Pharmacogenet Genomics 18:977–988

    Article  CAS  PubMed  Google Scholar 

  29. Banker DE, Cooper JJ, Fennell DA, Willman CL, Appelbaum FR, Cotter FE (2002) PK11195, a peripheral benzodiazepine receptor ligand, chemosensitizes acute myeloid leukemia cells to relevant therapeutic agents by more than one mechanism. Leuk Res 26:91–106

    Article  CAS  PubMed  Google Scholar 

  30. Hirsch T, Decaudin D, Susin SA et al (1998) PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection. Exp Cell Res 241:426–434

    Article  CAS  PubMed  Google Scholar 

  31. Oudard S, Carpentier A, Banu E et al (2003) Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme. J Neurooncol 63:81–86

    Article  PubMed  Google Scholar 

  32. Zisterer DM, Hance N, Campiani G, Garofalo A, Nacci V, Williams DC (1998) Antiproliferative action of pyrrolobenzoxazepine derivatives in cultured cells: absence of correlation with binding to the peripheral-type benzodiazepine binding site. Biochem Pharmacol 55:397–403

    Article  CAS  PubMed  Google Scholar 

  33. Gorman AM, O’Beirne GB, Regan CM, Williams DC (1989) Antiproliferative action of benzodiazepines in cultured brain cells is not mediated through the peripheral-type benzodiazepine acceptor. J Neurochem 53:849–855

    Article  CAS  PubMed  Google Scholar 

  34. Alexander BE, Roller E, Klotz U (1992) Characterization of peripheral-type benzodiazepine binding sites on human lymphocytes and lymphoma cell lines and their role in cell growth. Biochem Pharmacol 44:269–274

    Article  CAS  PubMed  Google Scholar 

  35. Hans G, Wislet-Gendebien S, Lallemend F et al (2005) Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression. Biochem Pharmacol 69:819–830

    Article  CAS  PubMed  Google Scholar 

  36. Scarf AM, Auman KM, Kassiou M (2012) Is there any correlation between binding and functional effects at the translocator protein (TSPO) (18 kDa)? Curr Mol Med 12:387–397

    CAS  PubMed  Google Scholar 

  37. Tummino PJ, Copeland RA (2008) Residence time of receptor-ligand complexes and its effect on biological function. Biochemistry 47:5481–5492

    Article  CAS  PubMed  Google Scholar 

  38. Guo D, Hillger JM, IJzerman AP, Heitman LH (2014) Drug-target residence time: a case for G protein-coupled receptors. Med Res Rev 34:856–892

    Article  CAS  PubMed  Google Scholar 

  39. Taliani S, Da Pozzo E, Bellandi M et al (2010) Novel irreversible fluorescent probes targeting the 18 kDa translocator protein: synthesis and biological characterization. J Med Chem 53:4085–4093

    Article  CAS  PubMed  Google Scholar 

  40. Primofiore G, Da Settimo F, Taliani S et al (2004) N, N-dialkyl-2-phenylindol-3-ylglyoxylamides. A new class of potent and selective ligands at the peripheral benzodiazepine receptor. J Med Chem 47:1852–1855

    Article  CAS  PubMed  Google Scholar 

  41. Chang-Liu CM, Woloschok GE (1997) Effect of passage number on cellular response to DNA-damaging agents: cell survival and gene expression. Cancer Lett 26:77–86

    Article  Google Scholar 

  42. Wenger SL, Senft JR, Sargent LM, Bamezai R, Bairwa N, Grant SG (2004) Comparison of established cell lines at different passages by karyotype and comparative genomic hybridization. Biosci Rep 24:631–639

    Article  CAS  PubMed  Google Scholar 

  43. Chelli B, Salvetti A, Da Pozzo E et al (2008) PK 11195 differentially affects cell survival in human wild-type and 18 kDa Translocator protein-silenced ADF astrocytoma cells. J Cell Biochem 105:712–723

    Article  CAS  PubMed  Google Scholar 

  44. Vandesompele J, De Paepe A, Speleman F (2002) Elimination of primer-dimer artifacts and genomic coamplification using a two-step SYBR green I real-time RT-PCR. Anal Biochem 303:95–98

    Article  CAS  PubMed  Google Scholar 

  45. Costa B, Salvetti A, Rossi L et al (2006) Peripheral benzodiazepine receptor: characterization in human T-lymphoma Jurkat cells. Mol Pharmacol 69:37–44

    CAS  PubMed  Google Scholar 

  46. Costa B, Bendinelli S, Gabelloni P et al (2013) Human glioblastoma multiforme: p53 reactivation by a novel MDM2 inhibitor. PLoS One 8:e72281

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Keats E, Khan ZA (2012) Unique responses of stem cell-derived vascular endothelial and mesenchymal cells to high levels of glucose. PLoS One 7:e38752

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Smiley ST, Reers M, Mottola-Hartshorn C et al (1991) Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA 88:3671–3675

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Di Lisa F, Blank PS, Colonna R et al (1995) Mitochondrial membrane potential in single living adult rat cardiac myocytes exposed to anoxia or metabolic inhibition. J Physiol 486:1–13

    Article  PubMed Central  PubMed  Google Scholar 

  50. Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA (2011) Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. Biotechniques 50:98–115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Stolarczyk M, Naruszewicz M, Kiss AK (2013) Extracts from Epilobium sp. herbs induce apoptosis in human hormone-dependent prostate cancer cells by activating the mitochondrial pathway. J Pharm Pharmacol 65:1044–1054

    Article  CAS  PubMed  Google Scholar 

  52. Agarwal C, Singh RP, Agarwal R (2002) Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis 23:1869–1876

    Article  CAS  PubMed  Google Scholar 

  53. Cossarizza A, Baccarani-Contri M, Kalashnikova G, Franceschi C (1993) A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem Biophys Res Commun 197:40–45

    Article  CAS  PubMed  Google Scholar 

  54. Fadok VA, Voelker DR, Campbell PA et al (1992) Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148:2207–2216

    CAS  PubMed  Google Scholar 

  55. Li B, Chauvin C, De Paulis D et al (2012) Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory site masked by cyclophilin D1. Biochim Biophys Acta 1817:1628–1634

    Article  CAS  PubMed  Google Scholar 

  56. Veenman L, Levin E, Weisinger G et al (2004) Peripheral-type benzodiazepine receptor density and in vitro tumorigenicity of glioma cell lines. Biochem Pharmacol 68:689–698

    Article  CAS  PubMed  Google Scholar 

  57. Giusti L, Costa B, Viacava P et al (2004) Peripheral type benzodiazepine receptor in human parathyroid glands: up-regulation in adenoma. J Endocrinol Invest 27:826–831

    Article  CAS  PubMed  Google Scholar 

  58. Boujrad N, Vidic B, Papadopoulos V (1996) Acute action of choriogonadotropin on Leydig tumor cells: changes in the topography of the mitochondrial peripheral-type benzodiazepine receptor. Endocrinology 137:5727–5730

    CAS  PubMed  Google Scholar 

  59. Delavoie F, Li H, Hardwick M et al (2003) In vivo and in vitro peripheral-type benzodiazepine receptor polymerization: functional significance in drug ligand and cholesterol binding. Biochemistry 42:4506–4519

    Article  CAS  PubMed  Google Scholar 

  60. Cleary J, Johnson KM, Opipari AW Jr, Glick GD (2007) Inhibition of the mitochondrial F1F0-ATPase by ligands of the peripheral benzodiazepine receptor. Bioorg Med Chem Lett 17:1667–1670

    Article  CAS  PubMed  Google Scholar 

  61. Bernardi P (1999) Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79:1127–1155

    CAS  PubMed  Google Scholar 

  62. Broaddus WC, Bennett JP Jr (1990) Peripheral-type benzodiazepine receptors in human glioblastomas: pharmacologic characterization and photoaffinity labeling of ligand recognition site. Brain Res 518:199–208

    Article  CAS  PubMed  Google Scholar 

  63. Lueddens HW, Newman AH, Rice KC, Skolnick P (1986) AHN 086: an irreversible ligand of “peripheral” benzodiazepine receptors. Mol Pharmacol 29:540–545

    CAS  PubMed  Google Scholar 

  64. Newman AH, Lueddens HW, Skolnick P, Rice KC (1987) Novel irreversible ligands specific for “peripheral” type benzodiazepine receptors: (±)-, (+)-, and (-)-1-(2-chlorophenyl)-N-(1-methylpropyl)-N-(2-isothiocyanatoethyl)-3-isoquinolinecarboxamide and 1-(2-isothiocyanatoethyl)-7-chloro-1,3-dihydro-5-(4-chlorophenyl)-2H-1,4-benzodiazepin-2-one. J Med Chem 30:1901–1905

    Article  CAS  PubMed  Google Scholar 

  65. McCabe RT, Schoenheimer JA, Skolnick P, Newman AH, Rice KC, Reig JA, Klein DC (1989) [3H]AHN 086 acylates peripheral benzodiazepine receptors in the rat pineal gland. FEBS Lett 244:263–267

    Article  CAS  PubMed  Google Scholar 

  66. Alenfall J, Batra S (1996) Photoaffinity labeling of peripheral benzodiazepine receptors in R-3327 Dunning prostatic tumors. Biochem Pharmacol 51:1009–1013

    Article  CAS  PubMed  Google Scholar 

  67. van Engeland M, Nieland LJ, Ramaekers FC et al (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31:1–9

    Article  PubMed  Google Scholar 

  68. Galluzzi L, Zamzami N, de La Motte Rouge T, Lemaire C, Brenner C, Kroemer G (2007) Methods for the assessment of mitochondrial membrane permeabilization in apoptosis. Apoptosis 12:803–813

    Article  CAS  PubMed  Google Scholar 

  69. Copeland RA, Pompliano DL, Meek TD (2006) Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discov 5:730–739

    Article  CAS  PubMed  Google Scholar 

  70. Guo D, Hillger JM, IJzerman AP, Heitman LH (2014) Drug-target residence time: a case for G protein-coupled receptors. Med Res Rev 34:856–892

    Article  CAS  PubMed  Google Scholar 

  71. Sutter AP, Maaser K, Gerst B, Krahn A, Zeitz M, Scherübl H (2004) Enhancement of peripheral benzodiazepine receptor ligand-induced apoptosis and cell cycle arrest of esophageal cancer cells by simultaneous inhibition of MAPK/ERK kinase. Biochem Pharmacol 67:1701–1710

    Article  CAS  PubMed  Google Scholar 

  72. Sileikyte J, Blachly-Dyson E, Sewell R et al (2014) Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (TSPO). J Biol Chem 289:13769–13781

    Article  CAS  PubMed  Google Scholar 

  73. Azarashvili T, Baburina Y, Grachev D et al (2014) Carbenoxolone induces permeability transition pore opening in rat mitochondria via the translocator protein TSPO and connexin43. Arch Biochem Biophys 558:87–94

    Article  CAS  PubMed  Google Scholar 

  74. Azarashvili T, Grachev D, Krestinina O et al (2007) The peripheral-type benzodiazepine receptor is involved in control of Ca2+-induced permeability transition pore opening in rat brain mitochondria. Cell Calcium 42:27–39

    Article  CAS  PubMed  Google Scholar 

  75. Li J, Wang J, Zeng Y (2007) Peripheral benzodiazepine receptor ligand, PK11195 induces mitochondria cytochrome c release and dissipation of mitochondria potential via induction of mitochondria permeability transition. Eur J Pharmacol 560:117–122

    Article  CAS  PubMed  Google Scholar 

  76. Pastorino JG, Simbula G, Gilfor E, Hoek JB, Farber JL (1994) Protoporphyrin IX, an endogenous ligand of the peripheral benzodiazepine receptor, potentiates induction of the mitochondrial permeability transition and the killing of cultured hepatocytes by rotenone. J Biol Chem 269:31041–31046

    CAS  PubMed  Google Scholar 

  77. Chelli B, Falleni A, Salvetti F, Gremigni V, Lucacchini A, Martini C (2001) Peripheral-type benzodiazepine receptor ligands: mitochondrial permeability transition induction in rat cardiac tissue. Biochem Pharmacol 61:695–705

    Article  CAS  PubMed  Google Scholar 

  78. Kinnally KW, Zorov DB, Antonenko YN, Snyder SH, McEnery MW, Tedeschi H (1993) Mitochondrial benzodiazepine receptor linked to inner membrane ion channels by nanomolar actions of ligands. Proc Natl Acad Sci USA 90:1374–1378

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Berson A, Descatoire V, Sutton A et al (2001) Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation. J Pharmacol Exp Ther 299:793–800

    CAS  PubMed  Google Scholar 

  80. Obame FN, Zini R, Souktani R, Berdeaux A, Morin D (2007) Peripheral benzodiazepine receptor-induced myocardial protection is mediated by inhibition of mitochondrial membrane permeabilization. Pharmacol Exp Ther 323:336–345

    Article  CAS  Google Scholar 

  81. Giorgio V, von Stockum S, Antoniel M et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci USA 110:5887–5892

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Seneviratne MS, Faccenda D, De Biase V, Campanella M (2012) PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells. Curr Mol Med 12:476–482

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding for this study was provided by the Italian Ministry of University and Scientific Research (PRIN-prot. 20098SJX4F; PRIN-prot. 2010W7YRLZ_005 and FIRB-prot. RBFR10ZJQT_002).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacy, University of Pisa, via Bonanno, 6-56126, Pisa, Italy

    Barbara Costa, Eleonora Da Pozzo, Chiara Giacomelli, Sabrina Taliani, Sara Bendinelli, Elisabetta Barresi, Federico Da Settimo & Claudia Martini

Authors
  1. Barbara Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eleonora Da Pozzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Giacomelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabrina Taliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sara Bendinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabetta Barresi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Federico Da Settimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Claudia Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Barbara Costa or Claudia Martini.

Additional information

Barbara Costa and Eleonora Da Pozzo have equally contributed to the work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Costa, B., Da Pozzo, E., Giacomelli, C. et al. TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance. Apoptosis 20, 383–398 (2015). https://doi.org/10.1007/s10495-014-1063-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-014-1063-3

Keywords

Search

Navigation