Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor

Oncogene volume 24, pages 7503–7513 (2005)Cite this article

Abstract

1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) is a prototypic ligand of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein. PK11195 can be used to chemosensitize tumor cells to a variety of chemotherapeutic agents, both in vitro and in vivo. PK11195 has been suggested to exert this effect via inhibition of the multiple drug resistance (MDR) pump and by direct mitochondrial effects which could be mediated by the PBR. Here, we established a model system in which PK11195 and another PBR ligand, 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (Ro5-4864), sensitize to nutrient depletion-induced cell death. In this MDR-independent model, PK11195 and Ro5-4864 are fully active even when the PBR is knocked down by small interfering RNA. Cells that lack PBR possess low-affinity binding sites for PK11195 and Ro5-4864. The starvation-sensitizing effects of PK11195 are not due to a modulation of the adaptive response of starved cells, namely autophagy and NF-κB activation. Rather, it appears that the combination of PK11195 with autophagy or NF-κB inhibitors has a potent synergistic death-inducing effect. Starved cells treated with PK11195 exhibit characteristics of apoptosis, including loss of the mitochondrial transmembrane potential, mitochondrial cytochrome c release, caspase activation and chromatin condensation. Accordingly, stabilization of mitochondria by overexpression of Bcl-2 or expression of the viral mitochondrial inhibitor (vMIA) from cytomegalovirus inhibits cell death induced by PK11195 plus starvation. Thus, PK11195 potently sensitizes to apoptosis via a pathway that involves mitochondria, yet does not involve the PBR.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

AV:

autophagic vacuoles

Casp3a:

activated caspase-3

Co:

control

Cyt c:

cytochrome c

ΔΨm:

mitochondrial transmembrane potential

DAPI:

4′,6-diamidino-2-phenylindole dihydrochloride

DiOC6(3):

3,3′dihexyloxacarbocyanine iodide

EMSA:

electrophoretic mobility shift assays

FSC:

forward scatter channel

HCQ:

hydroxychloroquine

Ho:

Hoechst 33342

3-MA:

3-methyladenine

IKSR:

inhibitor of NF-κB super-repressor

MDR:

multiple drug resistance

MMP:

mitochondrial membrane permeabilization

NGFR:

nerve cell growth factor receptor

PBR:

peripheral benzodiazepine receptor

PI:

propidium iodine

PK11195:

1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide

Ro5-4864:

7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Z-VAD-fmk:

N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone

References

  • Ansseau M, von Frenckell R, Cerfontaine JL and Pa-part P . (1991). Pharmacopsychiatry, 24, 8–12.

  • Banker DE, Cooper JJ, Fennell DA, Willman CL, Appelbaum FR and Cotter FE . (2002). Leuk. Res., 26, 91–106.

  • Baran-Marszak F, Feuillard J, Najjar I, Le Clorennec C, Bechet JM, Dusanter-Fourt I, Bornkamm GW, Raphael M and Fagard R . (2004). Blood, 104, 2475–2483.

  • Baron U, Freundlieb S, Gossen M and Bujard H . (1995). Nucleic Acids Res., 11, 3605–3606.

  • Belzacq AS, El Hamel C, Vieira HLA, Cohen I, Haouzi D, Metivier D, Marchetti P, Goldmacher V, Brenner C and Kroemer G . (2001). Oncogene, 20, 7579–7587.

  • Belzacq AS, Vieira HL, Verrier F, Vandecasteele G, Cohen I, Prevost MC, Petit PX, Kahn A, Roques B, Rizzuto R, Brenner C and Kroemer G . (2003). Cancer Res., 63, 541–546.

  • Boitano A, Ellman JA, Glick GD and Opipari AJ . (2003). Cancer Res., 63, 6870–6876.

  • Boya P, Gonzalez-Polo R-A, Casares N, Perfettini J-L, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Pierron G, Ohsumi Y, Codogno P and Kroemer G . (2005). Mol. Cell. Biol., 25, 1025–1040.

  • Boya P, Gonzalez-Polo R-A, Poncet D, Andreau K, Roumier T, Perfettini J-L and Kroemer G . (2003). Oncogene, 22, 3927–3936.

  • Carayon P, Portier M, Dussossoy D, Bord A, Petitpretre G, Canat X, Le Fur G and Casellas P . (1996). Blood, 87, 3170–3178.

  • Casellas P, Galiegue S and Basile AS . (2002). Neurochem. Int., 40, 475–486.

  • Castedo M, Perfettini J-L and Kroemer G . (2002). J. Exp. Med., 196, 1121–1126.

  • Chauhan D, Li G, Podar K, Hideshima T, Mitsiades C, Schlossman R, Munshi N, Richardson P, Cotter FE and Anderson K . (2004). Blood, 104, 2458–2466.

  • Chen J, Freeman A, Liu J, Dai Q and Lee RM . (2002). Mol. Cancer Ther., 1, 961–967.

  • Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Park DS, Dawson TM, Kroemer G and Slack RS . (2002). J. Cell Biol., 158, 507–517.

  • Decaudin D . (2004). Anticancer Drugs, 15, 737–745.

  • Decaudin D, Castedo M, Beurdeley-Thomas A, Nemati F, de Pinieux G, Caron A, Pouillart P, Wijdenes J, Rouillard D, Kroemer G and Poupon M-F . (2002). Cancer Res., 62, 1388–1393.

  • Fennell DA, Corbo M, Pallaska A and Cotter FE . (2001). Br. J. Cancer, 84, 1397–1404.

  • Ferry A, Jaillon P, Lecocq B, Lecocq V and Jozefczak C . (1989). Fundam. Clin. Pharmacol., 3, 383–392.

  • Feuillard J, Schuhmacher M, Kohanna S, Asso-Bonnet M, Ledeur F, Joubert-Caron R, Bissieres P, Polack A, Bornkamm GW and Raphael M . (2000). Blood, 95, 2068–2075.

  • Galiegue S, Casellas P, Kramar A, Tinel N and Simony-Lafontaine J . (2004). Clin. Cancer Res., 10, 2058–2064.

  • Goldmacher VS, Bartle LM, Skletskaya S, Dionne CA, Kedersha NL, Vater CA, Han JW, Lutz RJ, Watanabe S, McFarland EDC, Kieff ED, Mocarski ES and Chittenden T . (1999). Proc. Natl. Acad. Sci. USA, 96, 12536–12541.

  • Green DR and Kroemer G . (2004). Science, 305, 626–629.

  • Harborth J, Elbashir SM, Bechert K, Tuschl T and Weber K . (2001). J. Cell Sci., 114, 4557–4565.

  • Hirsch T, Decaudin D, Susin SA, Marchetti P, Larochette N, Resche-Rigon M and Kroemer G . (1998). Exp. Cell Res., 241, 426–434.

  • Jakubikova J, Duraj J, Hunakova L, Chorvath B and Sedlak J . (2002). Neoplasma, 49, 231–236.

  • Jorda EG, Jimenez A, Verdaguer E, Canudas AM, Folch J, Sureda FX, Camins A and Pallas M . (2005). Apoptosis, 10, 91–104.

  • Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y and Yoshimori T . (2000). EMBO J., 19, 5720–5728.

  • Kroemer G . (1997). Nat. Med., 3, 614–620.

  • Larochette N, Decaudin D, Jacotot E, Brenner C, Marzo I, Susin SA, Zamzami N, Xie Z, Reed JC and Kroemer G . (1999). Exp. Cell Res., 249, 413–421.

  • Lebedeva IV, Su ZZ, Sarkar D, Kitada D, Dent P, Waxman S, Reed JC and Fisher PB . (2003). Cancer Res., 63, 8138–8144.

  • Lum JJ, Bauer DE, Kong M, Harris HM, Li C and Lindsten T . (2005). Cell, 120, 237–248.

  • Maaser K, Grabowski P, Oezdem Y, Krahn A, Heine B, Stein H, Buhr H, Zeitz M and Scherubl H . (2005). Clin. Cancer Res., 11, 1751–1756.

  • McEnery MW, Snowman AM, Trifiletti RR and Snyder SH . (1992). Proc. Natl. Acad. Sci. USA, 89, 3170–3174.

  • Miccoli L, Beurdeley-Thomas A, De Pinieux G, Sureau F, Oudard S, Dutrillaux B and Poupon MF . (1998a). Cancer Res., 58, 5777–5786.

  • Miccoli L, Poirson-Bichat F, Sureau F, Gonçalves RB, Bourgeois Y, Dutrillaux B, Poupon M-F and Oudard S . (1998b). J. Natl. Cancer Inst., 90, 1400–1406.

  • Muscarella DE, O'Brien KA, Lemley AT and Bloom SE . (2003). Toxicol Sci., 74, 66–73.

  • Okaro AC, Fennell DA, Corbo M, Davidson BR and Cotter FE . (2002). Gut., 51, 556–561.

  • Pattingre S, Bauvy C and Codogno P . (2003). J. Biol. Chem., 278, 16667–16674.

  • Poncet D, Boya P, Larochette N, Jalil A-A, Paulau A-L, Cartron P-F, Vallette FM, Schnebelen C, Bartle LM, Skaleskaya A, Martinou J-C, Goldmacher VS, Kroemer G and Zamzami N . (2004). J. Biol. Chem., 279, 22605–22614.

  • Ravagnan L, Marzo I, Costantini P, Susin SA, Zamzami N, Petit PX, Hirsch F, Poupon M-F, Miccoli L, Xie Z, Reed JC and Kroemer G . (1999). Oncogene, 18, 2537–2546.

  • Rochard P, Galiegue S, Tinel N, Peleraux A, Bord A, Jbilo O and Casellas P . (2004). Gene Expr., 12, 13–27.

  • Shimizu S, Konishi A, Kodama T and Tsujimoto Y . (2000). Proc. Natl. Acad. Sci. USA, 97, 3100–3105.

  • Shimizu S, Matsuoka Y, Shinohara Y, Yoneda Y and Tsujimoto Y . (2001). J. Cell Biol., 152, 237–250.

  • Snyder SH, McEnery MW and Verma A . (1990). Neurochem. Res., 15, 119–123.

  • Sutter AP, Maaser K, Barthel B and Scherubl H . (2003). Br. J. Cancer, 89, 564–572.

  • Sutter AP, Maaser K, Grabowski P, Bradacs G, Vormbrock K, Hopfner M, Krahn A, Heine B, Stein H, Somasundaram R, Schuppan D, Zeitz M and Scherubl H . (2004). J. Hepatol., 41, 799–807.

  • Vieira HL, Haouzi D, El Hamel C, Belzacq AS, Brenner C and Kroemer G . (2000). Cell Death Differ., 7, 1146–1154.

  • Walter RB, Raden BW, Cronk MR, Bernstein ID, Appelbaum FR and Banker DE . (2004). Blood, 103, 4276–4284.

  • Weisinger G, Kelly-Hershkovitz E, Veenman L and Spanier I . (2004). Biochemistry, 43, 12315–12321.

Download references

Acknowledgements

We thank Dr T Yoshimori (National Institute for Basic Biology, Okazaki, Japan) for the LC3-GFP construct. Dr GK is supported by Cancéropôle Ile-de-France, Ligue Nationale contre le cancer, European Community (Active p53, RIGHT), and Sidaction. R-A G-P received a fellowship from the European Union (FP6-2002-5000698). IYM and JF are supported by Cancéropôle Grand-Sud-Ouest, Ligue Nationale contre le Cancer and Conseil Régional du Limousin.

Author information

Authors and Affiliations

  1. Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, Villejuif, 94805, France

    Rosa-Ana Gonzalez-Polo, Gabrielle Carvalho, Thorsten Braun, Claire Fabre, Nathanael Larochette, Jean-Luc Perfettini & Guido Kroemer

  2. Department of Hematology, Institut Curie, Paris, 75005, France

    Didier Decaudin

  3. Institut André Lwoff , INSERM U504, 16 avenue Paul-Vaillant-Couturier, Villejuif Cedex, 94807, France

    Mojgan Djavaheri-Mergny & Patrice Codogno

  4. Centre National de la Recherche Scientifique, UMR CNRS 6101 et Laboratoire d'Hématologie, faculté de Médicine et CHU Dupuytren, Limoges, France

    Ibtissam Youlyouz-Marfak & Jean Feuillard

  5. Service d'Hématologie Biologique, CHU Kremlin Bicêtre, U473, France

    Martine Raphael

Authors
  1. Rosa-Ana Gonzalez-Polo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabrielle Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thorsten Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Didier Decaudin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claire Fabre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nathanael Larochette
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean-Luc Perfettini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mojgan Djavaheri-Mergny
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ibtissam Youlyouz-Marfak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Patrice Codogno
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Martine Raphael
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean Feuillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Guido Kroemer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guido Kroemer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonzalez-Polo, RA., Carvalho, G., Braun, T. et al. PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor. Oncogene 24, 7503–7513 (2005). https://doi.org/10.1038/sj.onc.1208907

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208907

Keywords

This article is cited by

Search

Advanced search

Quick links