| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Department of Pharmacology and Therapeutics and the Shands Cancer Center, University of Florida, Gainesville, Florida and 2 Department of Cancer Biology and the Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
Requests for reprints: Brian Law, Department of Pharmacology and Therapeutics and the Shands Cancer Center, University of Florida, 1600 Southwest Archer Road, Box 100267, Gainesville, FL 32610. Phone: 352-392-3395; Fax: 352-392-9696; E-mail: bklaw{at}pharmacology.ufl.edu.
Rapamycin and its derivatives are promising anticancer agents, but the exact mechanisms by which these drugs induce cell cycle arrest and inhibit tumor growth are unknown. A biochemical analysis of human mammary tumor cell lines indicated that rapamycin-induced antiproliferative effects correlated with down-regulation of cellular p21 levels and the levels of p21 in cyclin-dependent kinase (Cdk) 2 and 4 complexes. Cyclin D1 overexpression reversed rapamycin action and this reversal correlated with increased levels of cellular p21, higher levels of p21 associated with Cdk2, and stabilization of cyclin D1/Cdk2/p21/proliferating cell nuclear antigen (PCNA) complexes. Experiments using a novel cyclin D1-Cdk2 fusion protein or a kinase-dead mutant of the fusion protein indicated that reversal of rapamycin action required not only the formation of complexes with p21 and PCNA but also complex-associated kinase activity. Similar results were observed in vivo. The rapamycin derivative RAD001 (everolimus) inhibited the growth of mouse mammary tumors, which correlated with the disruption of cyclin D1/Cdk2 complexes. The potential implications of these results with respect to the use of rapamycin derivatives in breast cancer therapy are discussed. (Cancer Res 2006; 66(2): 1070-80)
This article has been cited by other articles:
|
|
 |
|
  J. D. Mosley, J. T. Poirier, D. D. Seachrist, M. D. Landis, and R. A. Keri Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer Mol. Cancer Ther., August 1, 2007; 6(8): 2188 - 2197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Corsino, B. Davis, M. Law, A. Chytil, E. Forrester, P. Norgaard, N. Teoh, and B. Law Tumors Initiated by Constitutive Cdk2 Activation Exhibit Transforming Growth Factor {beta} Resistance and Acquire Paracrine Mitogenic Stimulation during Progression Cancer Res., April 1, 2007; 67(7): 3135 - 3144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cao, T. Subhawong, J. M. Albert, K. W. Kim, L. Geng, K. R. Sekhar, Y. J. Gi, and B. Lu Inhibition of Mammalian Target of Rapamycin or Apoptotic Pathway Induces Autophagy and Radiosensitizes PTEN Null Prostate Cancer Cells. Cancer Res., October 15, 2006; 66(20): 10040 - 10047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W.L. Yee, Z. Zeng, M. Konopleva, S. Verstovsek, F. Ravandi, A. Ferrajoli, D. Thomas, W. Wierda, E. Apostolidou, M. Albitar, et al. Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies Clin. Cancer Res., September 1, 2006; 12(17): 5165 - 5173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Brown, P. L. Zhang, M. Lun, S. Zhu, P. K. Pellitteri, A. Law, G. C. Wood, and T. L. Kennedy Morphoproteomic and Pharmacoproteomic Rationale for mTOR Effectors as Therapeutic Targets in Head and Neck Squamous Cell Carcinoma Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 273 - 282. [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 |
