Abstract
Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 24 print issues and online access
$259.00 per year
only $10.79 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Basu A, Haldar S (1998) Microtubule-damaging drugs triggered Bcl2 phosphorylation-requirement of phosphorylation on both serine-70 and serine-87 residues of Bcl2 protein. Int J Oncol 13: 659ā664
Bertrand R, Sarang M, Jenkin J, Kerrigan D, Pommier Y (1991) Differential induction of secondary fragmentation by topoisomerase II inhibitors in human tumor cell lines with amplified c-myc expression. Cancer Res 51: 6280ā6285
Brown JM, Wouters BG (1999) Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res 59: 1391ā1399
Cheng Q, Lee HH, Li Y, Parks TP, Cheng G (2000) Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-kappaB inhibition. Oncogene 19: 4936ā4940
EtiĆ©vant C, Barret J-M, Kruczynski A, Perrin D, Hill BT (1998) Vinflunine (20ā²,20ā²-difluoro-3ā²,4ā²-dihydrovinorelbine), a novel Vinca alkaloid, which participates in P-glycoprotein (Pgp)-mediated multidrug resistance in vivo and in vitro. Invest New Drugs 16: 3ā17
Fahy J, Duflos A, Ribet J-P, Jacquesy J-C, Berrier C, Jouannetaud M-P, Zunino F (1997) Vinca alkaloids in superacidic media: a method for creating a new family of antitumor derivatives. J Am Chem Soc 119: 8576ā8577
Fujita N, Tsuruo T (2000) In vivo veritas:Bcl-2 and bcl-X(L) mediate tumor cell resistance to chemotherapy. Drug Resist Update 3: 149ā154
Fumoleau P, Bennouna J, Raymond E, Armand T-P, Hocini A, Blanchot G, Delgado FM, Marty M (2000) Phase I clinical and pharmacokinetic trial of vinflunine (L0070) a novel fluorinated Vinca alkaloid in patients (pts) with advanced solid malignancies: Preliminary results. Proceedings of the 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy 576: 158
Germann UA (1996) P-glycoprotein-A mediator of multidrug resistance in tumour cells. Eur J Cancer 32A: 927ā944
Haldar S, Jena N, Croce CM (1995) Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci USA 92: 4507ā4511
Haldar S, Basu A, Croce CM (1997) Bcl2 is the guardian of microtubule integrity. Cancer Res 57: 229ā233
Hill BT, Fiebig HH, Waud WR, Poupon M-F, Colpaert F, Kruczynski A (1999) Superior in vivo experimental antitumour activity of vinflunine, relative to vinorelbine, in a panel of human tumour xenografts. Eur J Cancer 35: 512ā520
Hockenbery D, Nunez G, Milliman C (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348: 334ā336
JƤnicke RU, Spengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273: 9357ā9360
Kaufmann SC, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG (1993) Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res 53: 3976ā3985
Kruczynski A, Colpaert F, Tarayre J-P, Mouillard P, Fahy J, Hill BT (1998a) Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid. Cancer Chemother Pharmacol 41: 437ā447
Kruczynski A, Barret J-M, EtiĆ©vant C, Colpaert F, Fahy J, Hill BT (1998b) Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem Pharmacol 55: 635ā648
Lobert S, Ingram JW, Hill BT, Correia JJ (1998) A comparison of thermodynamic parameters for vinorelbine- and vinflunine- induced tubulin self-association by sedimentation velocity. Mol Pharmacol 53: 908ā915
Lowe SC, Bodis S, McClatchey A, Remington L, Ruley HE, Fischer DE, Housman DE, Jacks T (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266: 807ā810
Miller DK (1997) The role of the caspase family of cysteine proteases in apoptosis. Semin Immunol 9: 35ā49
Mooberry SL, Busquets L, Tien G (1997) Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent. Int J Cancer 73: 440ā448
Osborn MT, Chambers TC (1996) Role of the stress-activated/c-Jun NH2-terminal protein pathway in the cellular response to doxorubicin and other chemotherapeutic drugs. J Biol Chem 271: 30950ā30955
Rupnow BA, Murtha AD, Alarcon RM, Giaccia AJ, Knox SJ (1998) Direct evidence that apoptosis enhances tumor responses to fractionated radiotherapy. Cancer Res 58: 1779ā1784
Srivastava RK, Srivastava AR, Korsmeyer SJ, Nesterova M, Cho-Chung YS, Longo DL (1998) Involvement of microtubules in the regulation of Bcl2 phosphorylation and apoptosis through cyclic AMP-dependent protein kinase. Mol Cell Biol 18: 3509ā3517
Stoetzer OJ, Pogrebniak A, Scholz M, Pelka-Fleischer R, Gullis E, Darsow M, Nussler V, Wilmanns W (1999) Drug-induced apoptosis in chronic lymphocytic leukemia. Leukemia 13: 1873ā1880
Stone AA, Chambers TC (2000) Microtubule inhibitors elicit differential effects on MAP kinase (JNK, ERK, and p38) signalling pathways in human KB-3 carcinoma cells. Exp Cell Res 254: 110ā119
Toh HC, Sun L, Koh CH, Aw SE (1998) Vinorelbine induces apoptosis and caspase-3 (CPP32) expression in leukemia and lymphoma cells: a comparison with vincristine. Leukemia and Lymphoma 31: 195ā208
Torres K, Horwitz SB (1998) Mechanisms of taxol-induced cell death are concentration dependent. Cancer Res 58: 3620ā3626
Wang CY, Gutteridge DC, Mayo MW, Baldwin ASJ (1999a) NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol 19: 5923ā5929
Wang LG, Liu XM, Kreis W, Budman DR (1999b) The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review. Cancer Chemother Pharmacol 44: 355ā361
Wang T-H, Wang H-S, Ichijo H, Giannakakou P, Foster JS, Fojo T, Wimalasena J (1998) Microtubule-interfering agents activate c-Jun N-terminal kinase/stress-activated protein kinase through both ras and apoptosis signal-regulating kinase pathways. J Biol Chem 273: 4928ā4936
Wyllie AH (1997) Apoptosis: an overview. Br Med Bull 53: 451ā465
Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B (2000) Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells. J Biol Chem 275: 11092ā11099
Acknowledgements
We thank Nathalie Cabrol, Jacqueline Astruc, Eric Chazottes, ValƩrie Cassabois and StƩphane Gras for their skilled technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kruczynski, A., EtiĆ©vant, C., Perrin, D. et al. Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development. Br J Cancer 86, 143ā150 (2002). https://doi.org/10.1038/sj.bjc.6600025
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6600025
Keywords
This article is cited by
-
Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents
Cancer Chemotherapy and Pharmacology (2009)
-
Murine leukemia P388 vinorelbine-resistant cell lines are sensitive to vinflunine
Investigational New Drugs (2008)
-
Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia
British Journal of Cancer (2007)
-
Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy
British Journal of Cancer (2006)
-
Phase I study of Vinflunine administered as a 10-minute infusion on days 1 and 8 every 3 weeks
Investigational New Drugs (2006)