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:

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

Oncogene volume 21, pages 7533–7544 (2002)Cite this article

Abstract

Aplidin™, a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. Aplidin™ effectively inhibits cell viability by triggering a canonical apoptotic program resulting in alterations in cell morphology, caspase activation, and chromatin fragmentation. Pro-apoptotic concentrations of Aplidin™ induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK and a biphasic activation of ERK. Inhibition of JNK and p38 MAPK blocks the apoptotic program induced by Aplidin™, demonstrating its central role in the integration of the cellular stress induced by the drug. JNK and p38 MAPK activation results in downstream cytochrome c release and activation of caspases -9 and -3 and PARP cleavage, demonstrating the mediation of the mitochondrial apoptotic pathway in this process. We also demonstrate that protein kinase C delta (PKC-δ) mediates the cytotoxic effect of Aplidin™ and that it is concomitantly processed and activated late in the apoptotic process by a caspase mediated mechanism. Remarkably, cells deficient in PKC-δ show enhanced survival upon drug treatment as compared to its wild type counterpart. PKC-δ thus appears as an important component necessary for full caspase cascade activation and execution of apoptosis, which most probably initiates a positive feedback loop further amplifying the apoptotic process.

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
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

References

  • Anderson P . 1997 Microbiol. Mol. Biol. Rev. 61: 33–46

  • Anthoney A, Paz-Ares L, Twelves C, Cortes-Funes H, Kaye S, Pronk L, Celli N, Lopez-Lazaro L, Guzman C, Jimeno J . 2000 J. Clin. Oncol. 19: Suppl 734a

  • Armand JP, Ady-Vago N, Faivre S, Chieze S, Baudin E, Ribrag V, Lecot F, Iglesias L, Lopez-Lazaro L, Guzman C, Jimeno J, Ducreux M, Le Chevalier T, Raymond E . 2001 Proc. Am. Soc. Clin. Oncol. 20: (abstract 477)

  • Bacus SS, Gudkov AV, Lowe M, Lyass L, Yung Y, Komarov AP, Keyomarsi K, Yarden Y, Seger R . 2001 Oncogene 20: 147–155

  • Bharti A, Kraeft SK, Grounder M, Pandey P, Jin S, Yuam ZM, Lees-Miler SP, Weichselbaum R, Weaver D, Chen LB, Kufe D, Kharbanda S . 1998 Mol. Cell. Biol. 18: 6719–6728

  • Bowman A, Izquierdo MA, Jodrell D, Martinez M, Cicchella B, Jimeno J, Guzman C, Germa-Lluch J, Celli N, Smyth J . 2001 Proc. Am. Soc. Clin. Oncol. 20: (abstract 476)

  • Brenner B, Koppenhoefer U, Weinstock C, Linderkamp O, Lang F, Gulbins E . 1997 J. Biol. Chem. 272: 22173–22181

  • Broggini M, Marchini S, D'Incalci M, Taraboletti G, Giavazzi R, Faircloth G, Jimeno J . 2000 Proc. 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, (abstract 214)

  • Chen Y, Wang W, Kong AN, Tan TH . 1998 J. Biol. Chem. 273: 1769–1775

  • Chen Y, Wang X, Templeton D, Davis RJ, Tan TH . 1996a J. Biol. Chem. 271: 31929–31936

  • Chen YR, Meyer CF, Tan TH . 1996b J. Biol. Chem. 271: 631–634

  • Chen Z, Seimiya H, Naito M, Mashim T, Kizaki A, Dan S, Imauzumi M, Ichijo H, Miyazono K, Tsuruo T . 1999 Oncogene 18: 173–180

  • Ciruelos EM, Twelves C, Dominguez MJ, Anthony A, Castellanos D, Bezares S, Ruiz A, Lopez-Lazaro L, Jimeno J, Celli C, Cortes-Funes H, Paz-Ares L . 2002 Proc. Am. Soc. Clin. Oncol. 20: (abstract 442)

  • Cowan DB, Poutias DN, del Nido PJ, McGowan FXJ . 2000 Am. J. Physiol. Heart Circ. Physiol. 279: H619–H629

  • Crews CM, Collins JL, Lane WS, Snapper ML, Schreiber SL . 1994 J. Biol. Chem. 269: 15411–15414

  • Crews CM, Lane WS, Schreiber SL . 1996 Proc. Natl. Acad. Sci. USA 93: 4316–4319

  • Cross T, Griffiths G, Deacon E, Sallis R, Gough M, Watters D, Lod JM . 2000 Oncogene 19: 2331–2337

  • Ding W, Templeton DM . 2000 Toxicol. Appl. Pharmacol. 162: 93–99

  • English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S, Cobb MH . 1999 Exp. Cell Res. 253: 255–270

  • Erba E, Bassano L, Di Liberti G, Muradore I, Codegoni AM, Celli N, D'Incalci M . 1999 Proc. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, (abstract 312)

  • Faircloth G, Grant W, Jimeno J, Meely K, Rinehart KL . 1998 Proc. Am. Assoc. Cancer Res. 39: (abstract 1551)

  • Faircloth G, Grant W, Nam S, Jimeno J, Manzanares I, Rinehart KL . 1999 Proc. Am. Assoc. Cancer Res. 40: (abstract 2612)

  • Figueroa-Masot XA, Hetman M, Higgins MJ, Kokot N, Xia Z . 2001 J. Neurosci. 21: 4657–4667

  • Grubb DR, Ly JD, Vaillant F, Johnson KL, Lawen A . 2001 Oncogene 20: 4085–4094

  • Gschwend M, Müller H, Kielbassa K, Zang R, Kittstein W, Rincke G, Marcks F . 1994 Biochem. Biophys. Res. Commun. 199: 93–98

  • Gschwendt M . 1999 Eur. J. Biochem. 259: 555–564

  • Hagemann C, Blank JL . 2001 Cell Signal 13: 863–875

  • Hay E, Lemonnier J, Fromigue O, Marie PJ . 2001 J. Biol. Chem. 276: 29028–29036

  • Herr I, Debatin KM . 2001 Blood 98: 2603–2614

  • Herr I, Wilhelm D, Bohler T, Angel P, Debatin KM . 1997 EMBO J. 16: 6200–6208

  • Hisamoto K, Ohmichi M, Kanda Y, Adachi K, Nishio Y, Hayakawa J, Mabuchi S, Takahashi K, Tasaka K, Miyamoto Y, Taniguchi N, Murata Y . 2001 J. Biol. Chem. 276: 47642–47649

  • Hofmann J . 2001 Rev. Physiol. Biochem. Pharmacol. 142: 1–96

  • Huang C, Ma WY, Li J, Dong Z . 1999 Cancer Res. 59: 3053–3058

  • Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Tagaki M, Matsumoto K, Miyazono K, Gotoh Y . 1997 Science 275: 90–94

  • Jacobson MD, Weil MRM . 1997 Cell 88: 347–354

  • Kang Y, Park JS, Kim S, Shin YJ, Kim W, Joo HJ, Chun JS, Kim HJ, Ha MJ . 2000 Mol. Cell. Biol. Res. Commun. 4: 181–187

  • Koji U, Mihoko S, Yuko N, Yasuyoshi T, Yoshimasa N, Toshihiko O . 1999 J. Biol. Chem. 274: 2234–2242

  • Kroemer G . 1997 Nat. Med. 3: 614–620

  • Krupinski J, Lopez E, Marti E, Ferrer I . 2000 Neurobiol. Dis. 7: 332–342

  • Kummer JL, Rao PK, Heidenreich KA . 1997 J. Biol. Chem. 272: 20490–20494

  • Leszczynski D . 1995 Oncol. Res. 7: 471–480

  • Lucas M, Sánchez-Margalet V . 1995 Gen. Pharmacol. 26: 881–887

  • Luo Y, Umegaki H, Wang X, Abe R, Roth GS . 1998 J. Biol. Chem. 273: 3756–3764

  • Marshall CJ . 1995 Cell 80: 179–185

  • Mauroun JA, Goel R, Stewart DJ, Tomiak E, Belanger K, Soulieres D, Charpentier D, Seymour L, Matthews S, Jimeno J, Guzman C . 2001 Proc. Am. Soc. Clin. Oncol. 20: (abstract 2082)

  • Miyamoto Y, Nakayama K, Imaki H, Hirose S, Jiang Y, Aba M, Tsukiyama T, Nagahama H, Ohno S, Hatakeyama S, Nakayama KI . 2002 Nature 416: 865–869

  • Miyanishi K, Takayama T, Ohi M, Hayashi T, Nobuoka A, Nakajima T, Takimoto R, Kogawa K, Kato J, Sakamaki S, Niitsu Y . 2001 Gastroenterology 121: 865–874

  • Mizuno K, Noda K, Araki T, Imaoka T, Kobayashi Y, Akita Y, Shimonaka M, Kishi S, Ohno S . 1997 Eur. J. Biochem. 250: 7–18

  • Nuñez G, Benedict MA, Hu Y, Inohara N . 1998 Oncogene 17: 3237–3245

  • Osborn MT, Chambers TC . 1996 J. Biol. Chem. 271: 30950–30955

  • Persons DL, Yazlovitskaya EM, Cui W, Pelling JC . 1999 Clin. Cancer Res. 5: 1007–1014

  • Poot M, Teubert H, Rabinovitch PS, Kavanagh TJ . 1995 J. Cell Physiol. 163: 555–560

  • Powell CT, Brittis NJ, Stec D, Hug H, Heston WD, Fair WR . 1996 Cell Growth Differ. 7: 419–428

  • Rao L, White E . 1997 Curr. Opin. Genet. Dev. 7: 52–58

  • Reusch HP, Schaefer M, Plum C, Schultz G, Paul M . 2001 J. Biol. Chem. 276: 19540–19547

  • Reyland ME, Anderson SM, Matassa AA, Barzen KA, Quissell DO . 1999 J. Biol. Chem. 274: 19115–19123

  • Rinehart KL . 2000 Med. Res. Rev. 20: 1–27

  • Robinson MJ, Cobb MH . 1997 Curr. Opin. Cell Biol. 8: 180–186

  • Sambrook J, Fritsch EF, Maniatis T . 1989 Molecular Cloning: A Laboratory Manual New York: Cold Spring Harbor Laboratory Press

    Google Scholar 

  • Sánchez A, Alvarez AM, Benito M, Fabregat I . 1996 J. Biol. Chem. 271: 7416–7422

  • Schaeffer HJ, Weber MJ . 1999 Mol. Cell Biol. 19: 2435–2444

  • Schnelldorfer T, Gansauge S, Gansauge F, Schlosser S, Beger HG, Nussler AK . 2000 Cancer 89: 1440–1447

  • Schwenger P, Bellosta P, Vietor I, Basilico C, Skolnik EY, Vilcek J . 1997 Proc. Natl. Acad. Sci. USA 94: 2869–2873

  • Seger R, Krebs EG . 1995 FASEB J. 9: 726–735

  • Seimiya H, Mashimo T, Toho M, Tsuruo T . 1997 J. Biol. Chem. 272: 4631–4636

  • Shao RG, Cao CX, Pommier Y . 1997 J. Biol. Chem. 272: 31321–31325

  • Shtil AA, Mandlekar S, Yu R, Walter RJ, Hagen K, Tan TH, Roninson IB, Kong AN . 1999 Oncogene 18: 377–384

  • Stempka L, Schnölzer M, Rincke G, Marks F, Gschwendt M . 1998 In ASBMB Symposium on Protein Kinase C and Cellular Function, (abstract 33)

  • Tewari M, Quan LT, O'Rouke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM . 1995 Cell 81: 801–809

  • Thompson CB . 1995 Science 267: 1456–1462

  • Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, Ohno S . 1996 J. Biol. Chem. 271: 23512–23519

  • Whelan RD, Hosking LK, Townsend AJ, Cowan KH, Hill BT . 1989 Cancer Commun. 1: 359–365

  • Wyllie AH, Kerr JF, Currie AR . 1980 Int. Rev. Cytol. 68: 251–306

  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . 1995 Science 270: 1326–1331

  • Yu R, Jiao JJ, Duh JL, Tan TH, Kong AN . 1996a Cancer Res. 56: 2954–2959

  • Yu R, Shtil AA, Tan TH, Roninson IB, Kong AN . 1996b Cancer Lett. 107: 73–81

  • Yu W, Liao QY, Hantash FM, Sanders BG, Kline K . 2001 Cancer Res. 61: 6569–6576

  • Zhao X, Gschwend JE, Powell CT, Foster RG, Day KC, Day ML . 1997 J. Biol. Chem. 272: 22751–22757

Download references

Acknowledgements

We would like to thank Juan M López-Oliva for excellent technical assistance and members of the R+D Department of PharmaMar, S.A. We also thank Drs Simon Munt and José Antonio López-Martín for critical reading of the manuscript and fruitful suggestions.

Author information

Author notes

  1. Luis F García-Fernández and Alejandro Losada: Luis F García-Fernández and Alejandro Losada contributed equally to this work

Authors and Affiliations

  1. Drug Discovery Department, PharmaMar, S.A., E-28760 Tres Cantos, Madrid, Spain

    Luis F García-Fernández, Alejandro Losada, Victoria Alcaide, José María Fernández-Sousa & José María Sánchez-Puelles

  2. Centro de Citometría de Flujo, Facultad de Farmacia, Universidad Complutense, Madrid, E-28040, Spain

    Alberto M Álvarez

  3. Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (UAM-CSIC), Madrid, E-28029, Spain

    Ana Cuadrado, Laura González & Alberto Muñoz

  4. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Keiko Nakayama

  5. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Keiichi I Nakayama

Authors
  1. Luis F García-Fernández
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alejandro Losada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victoria Alcaide
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alberto M Álvarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Cuadrado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura González
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keiko Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Keiichi I Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. José María Fernández-Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alberto Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. José María Sánchez-Puelles
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José María Sánchez-Puelles.

Rights and permissions

Reprints and permissions

About this article

Cite this article

García-Fernández, L., Losada, A., Alcaide, V. et al. Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ. Oncogene 21, 7533–7544 (2002). https://doi.org/10.1038/sj.onc.1205972

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205972

Keywords

This article is cited by

Search

Advanced search

Quick links