| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
1 Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute University of South Florida, Tampa, Florida, and 2 Novartis Pharmaceutical, Inc., East Hanover, New Jersey
Presence of the activating length mutation (LM) in the juxtamembrane domain or point mutation in the kinase domain of FMS-like tyrosine kinase-3 (FLT-3) mediates ligand-independent progrowth and prosurvival signaling in approximately one-third of acute myelogenous leukemia (AML). PKC412, an inhibitor of FLT-3 kinase activity, is being clinically evaluated in AML. Present studies demonstrate that treatment of human acute leukemia MV4-11 cells (containing a FLT-3 LM) with the heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin (17-AAG) attenuated the levels of FLT-3 by inhibiting its chaperone association with heat shock protein 90, which induced the poly-ubiquitylation and proteasomal degradation of FLT-3. Treatment with 17-AAG induced cell cycle G1 phase accumulation and apoptosis of MV4-11 cells. 17-AAG-mediated attenuation of FLT-3 and p-FLT-3 in MV4-11 cells was associated with decrease in the levels of p-AKT, p-ERK1/2, and p-STAT5, as well as attenuation of the DNA binding activity of STAT-5. Treatment with 17-AAG, downstream of STAT5, reduced the levels of c-Myc and oncostatin M, which are transactivated by STAT5. Cotreatment with 17-AAG and PKC412 markedly down-regulated the levels of FLT-3, p-FLT-3, p-AKT, p-ERK1/2, and p-STAT5, as well as induced more apoptosis of MV4-11 cells than either agent alone. Furthermore, the combination of 17-AAG and PKC412 exerted synergistic cytotoxic effects against MV4-11 cells. Importantly, 17-AAG and PKC412 induced more loss of cell viability of primary AML blasts containing FLT-3 LM, as compared with those that contained wild-type FLT-3. Collectively, these in vitro findings indicate that the combination of 17-AAG and PKC412 has high level of activity against AML cells with FLT-3 mutations.
This article has been cited by other articles:
|
|
 |
|
  R. M. Stone Genetically Defined Prognostic Factors and Novel Therapeutics for AML ASCO Educational Book, January 1, 2008; 2008(1): 280 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. F. Peterson, A. Boyapati, E.-Y. Ahn, J. R. Biggs, A. J. Okumura, M.-C. Lo, M. Yan, and D.-E. Zhang Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts Blood, August 1, 2007; 110(3): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Yao, B. Weigel, and J. Kersey Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51 Clin. Cancer Res., March 1, 2007; 13(5): 1591 - 1600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sharkey, T. Khong, and A. Spencer PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells Blood, February 15, 2007; 109(4): 1712 - 1719. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Chen, V. Gandhi, and W. Plunkett A Sequential Blockade Strategy for the Design of Combination Therapies to Overcome Oncogene Addiction in Chronic Myelogenous Leukemia. Cancer Res., November 15, 2006; 66(22): 10959 - 10966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bauer, L. K. Yu, G. D. Demetri, and J. A. Fletcher Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res., September 15, 2006; 66(18): 9153 - 9161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Teicher Protein kinase C as a therapeutic target. Clin. Cancer Res., September 15, 2006; 12(18): 5336 - 5345. [Full Text] [PDF]
|
|
|
|
|
|
F. Heidel, F. K. Solem, F. Breitenbuecher, D. B. Lipka, S. Kasper, M. H. Thiede, C. Brandts, H. Serve, J. Roesel, F. Giles, et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain Blood, January 1, 2006; 107(1): 293 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Guo, K. Rocha, P. Bali, M. Pranpat, W. Fiskus, S. Boyapalle, S. Kumaraswamy, M. Balasis, B. Greedy, E. S. M. Armitage, et al. Abrogation of Heat Shock Protein 70 Induction as a Strategy to Increase Antileukemia Activity of Heat Shock Protein 90 Inhibitor 17-Allylamino-Demethoxy Geldanamycin Cancer Res., November 15, 2005; 65(22): 10536 - 10544. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Carbone, J. A. Doorn, Z. Kiebler, B. R. Ickes, and D. R. Petersen Modification of Heat Shock Protein 90 by 4-Hydroxynonenal in a Rat Model of Chronic Alcoholic Liver Disease J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 8 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Castro, C. E. Prada, O. Loria, A. Kamal, L. Chen, F. J. Burrows, and T. J. Kipps ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia Blood, October 1, 2005; 106(7): 2506 - 2512. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Tussiwand, N. Onai, L. Mazzucchelli, and M. G. Manz Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity J. Immunol., September 15, 2005; 175(6): 3674 - 3680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bali, M. Pranpat, J. Bradner, M. Balasis, W. Fiskus, F. Guo, K. Rocha, S. Kumaraswamy, S. Boyapalle, P. Atadja, et al. Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90: A NOVEL BASIS FOR ANTILEUKEMIA ACTIVITY OF HISTONE DEACETYLASE INHIBITORS J. Biol. Chem., July 22, 2005; 280(29): 26729 - 26734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-E. Schmidt-Arras, A. Bohmer, B. Markova, C. Choudhary, H. Serve, and F.-D. Bohmer Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases Mol. Cell. Biol., May 1, 2005; 25(9): 3690 - 3703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Boeckman, K. S. Trego, and J. J. Turchi Cisplatin Sensitizes Cancer Cells to Ionizing Radiation via Inhibition of Nonhomologous End Joining Mol. Cancer Res., May 1, 2005; 3(5): 277 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Chen and W. Plunkett Sequential Blockade of Oncogenic Kinases Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 344 - 348. [Full Text] [PDF]
|
|
|
|
|
|
P. George, P. Bali, S. Annavarapu, A. Scuto, W. Fiskus, F. Guo, C. Sigua, G. Sondarva, L. Moscinski, P. Atadja, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3 Blood, February 15, 2005; 105(4): 1768 - 1776. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
