| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets and Chemical Biology |
Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey
Requests for reprints: Lyubomir T. Vassilev, Discovery Oncology, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110. Phone: 973-235-8106; Fax: 973-235-6185; E-mail: lyubomir.vassilev{at}roche.com.
Recent studies have shown that activation of cell cycle checkpoints can protect normal proliferating cells from mitotic inhibitors by preventing their entry into mitosis. These studies have used genotoxic agents that act, at least in part, by activation of the p53 pathway. However, genotoxic drugs are known also to have p53-independent activities and could affect the sensitivity of tumor cells to antimitotic agents. Recently, we have developed the first potent and selective small-molecule inhibitors of the p53-MDM2 interaction, the nutlins, which activate the p53 pathway only in cells with wild-type but not mutant p53. Using these compounds, we show that p53 activation leads to G1 and G2 phase arrest and can protect cells from mitotic block and apoptosis caused by paclitaxel. Pretreatment of HCT116 and RKO colon cancer cells (wild-type p53) or primary human fibroblasts (1043SK) with nutlins for 24 hours followed by incubation with paclitaxel for additional 48 hours did not increase significantly their mitotic index and protected the cells from the cytotoxicity of paclitaxel. Cancer cells with mutant p53 (MDA-MB-435) responded to the same treatment with mitotic arrest and massive apoptosis. These results have two major implications for cancer therapy. First, p53-activating therapies may have antagonistic effect when combined with mitotic poisons. Second, pretreatment with MDM2 antagonists before chemotherapy of tumors with mutant p53 may offer a partial protection to proliferating normal tissues.
Key Words: p53 • MDM2 • cell cycle • paclitaxel • chemoprotection
This article has been cited by other articles:
|
|
 |
|
  H. Shen, D. M. Moran, and C. G. Maki Transient Nutlin-3a Treatment Promotes Endoreduplication and the Generation of Therapy-Resistant Tetraploid Cells Cancer Res., October 15, 2008; 68(20): 8260 - 8268. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shangary and S. Wang Targeting the MDM2-p53 Interaction for Cancer Therapy Clin. Cancer Res., September 1, 2008; 14(17): 5318 - 5324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Jones, Q. Chen, P. M. Voorhees, K. H. Young, N. Bruey-Sedano, D. Yang, and R. Z. Orlowski Inhibition of the p53 E3 Ligase HDM-2 Induces Apoptosis and DNA Damage-Independent p53 Phosphorylation in Mantle Cell Lymphoma Clin. Cancer Res., September 1, 2008; 14(17): 5416 - 5425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lu, A. Strohecker, F. Chen, T. Kwan, J. Bosman, V. C. Jordan, and V. L. Cryns Aspirin Sensitizes Cancer Cells to TRAIL-Induced Apoptosis by Reducing Survivin Levels Clin. Cancer Res., May 15, 2008; 14(10): 3168 - 3176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chatterjee, C. Rancso, T. Stuhmer, N. Eckstein, M. Andrulis, C. Gerecke, H. Lorentz, H.-D. Royer, and R. C. Bargou The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma Blood, April 1, 2008; 111(7): 3714 - 3722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Cheok, A. Dey, and D. P. Lane Cyclin-Dependent Kinase Inhibitors Sensitize Tumor Cells to Nutlin-Induced Apoptosis: a Potent Drug Combination Mol. Cancer Res., November 1, 2007; 5(11): 1133 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Das, K. Vaiphei, D. Jain, and Jai Dev Wig p53 and mdm2 Expression in Colorectal Carcinoma: A Correlative Analysis With Clinical Staging and Histological Parameters International Journal of Surgical Pathology, October 1, 2007; 15(4): 335 - 345. [Abstract] [PDF]
|
|
|
|
|
|
A. Efeyan, A. Ortega-Molina, S. Velasco-Miguel, D. Herranz, L. T. Vassilev, and M. Serrano Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin Cancer Res., August 1, 2007; 67(15): 7350 - 7357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Drakos, A. Thomaides, L. J. Medeiros, J. Li, V. Leventaki, M. Konopleva, M. Andreeff, and G. Z. Rassidakis Inhibition of p53-Murine Double Minute 2 Interaction by Nutlin-3A Stabilizes p53 and Induces Cell Cycle Arrest and Apoptosis in Hodgkin Lymphoma Clin. Cancer Res., June 1, 2007; 13(11): 3380 - 3387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Bernal and A. Hernandez p53 Stabilization can be Uncoupled from its Role in Transcriptional Activation by Loss of PTTG1/Securin J. Biochem., May 1, 2007; 141(5): 737 - 745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jiang, N. Pabla, R. F. Murphy, T. Yang, X.-M. Yin, K. Degenhardt, E. White, and Z. Dong Nutlin-3 Protects Kidney Cells during Cisplatin Therapy by Suppressing Bax/Bak Activation J. Biol. Chem., January 26, 2007; 282(4): 2636 - 2645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Secchiero, F. Corallini, A. Gonelli, R. Dell'Eva, M. Vitale, S. Capitani, A. Albini, and G. Zauli Antiangiogenic Activity of the MDM2 Antagonist Nutlin-3 Circ. Res., January 5, 2007; 100(1): 61 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Levesque and A. Eastman p53-based cancer therapies: is defective p53 the Achilles heel of the tumor? Carcinogenesis, January 1, 2007; 28(1): 13 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kranz and M. Dobbelstein Nongenotoxic p53 Activation Protects Cells against S-Phase-Specific Chemotherapy Cancer Res., November 1, 2006; 66(21): 10274 - 10280. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kojima, M. Konopleva, T. McQueen, S. O'Brien, W. Plunkett, and M. Andreeff Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia Blood, August 1, 2006; 108(3): 993 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. T. Vassilev, C. Tovar, S. Chen, D. Knezevic, X. Zhao, H. Sun, D. C. Heimbrook, and L. Chen Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1 PNAS, July 11, 2006; 103(28): 10660 - 10665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Secchiero, E. Barbarotto, M. Tiribelli, C. Zerbinati, M. G. di Iasio, A. Gonelli, F. Cavazzini, D. Campioni, R. Fanin, A. Cuneo, et al. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL) Blood, May 15, 2006; 107(10): 4122 - 4129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kojima, M. Konopleva, I. J. Samudio, M. Shikami, M. Cabreira-Hansen, T. McQueen, V. Ruvolo, T. Tsao, Z. Zeng, L. T. Vassilev, et al. MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy Blood, November 1, 2005; 106(9): 3150 - 3159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. N. Demidenko, D. Halicka, J. Kunicki, J. A. McCubrey, Z. Darzynkiewicz, and M. V. Blagosklonny Selective Killing of Adriamycin-Resistant (G2 Checkpoint-Deficient and MRP1-Expressing) Cancer Cells by Docetaxel Cancer Res., May 15, 2005; 65(10): 4401 - 4407. [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 |
