This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saab, R. Articles by Skapek, S. X. Search for Related Content PubMed PubMed Citation Articles by Saab, R. Articles by Skapek, S. X.

Research Articles: Therapeutics

Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells

¹ Departments of Hematology/Oncology, ² Pathology, and ³ Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee; and ⁴ Pfizer Global R&D, Pfizer, Inc., Ann Arbor, Michigan

Requests for reprints: Stephen X. Skapek, Department of Hematology/Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105. Phone: 901-495-4019. E-mail: steve.skapek{at}stjude.org

Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology. Cyclin D–dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines. Cdk4 was expressed in 73% of alveolar and embryonal rhabdomyosarcoma tumors evaluated using a human tissue microarray. When challenged to differentiate by mitogen deprivation in vitro, mouse C2C12 myoblasts arrested in G₁ phase of the cell cycle, whereas four in the panel of rhabdomyosarcoma cell lines failed to do so. C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G₁ cell cycle phase. Similar treatment of rhabdomyosarcoma cell lines caused G₁ arrest and prevented cell accumulation in vitro, and it delayed growth of rhabdomyosarcoma xenografts in vivo. Consistent with a role for Cdk4/Cdk6 activity as a regulator of myogenic differentiation, we observed that PD 0332991 exposure promoted morphologic changes and enhanced the expression of muscle-specific proteins in cultured myoblasts and in the Rh30 cell line. Our findings support the concept that pharmacologic inhibition of Cdk4/Cdk6 may represent a useful therapeutic strategy to control cell proliferation and possibly promote myogenic differentiation in rhabdomyosarcoma. [Mol Cancer Ther 2006;5(5):1299–308]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: R. Saab and J.L. Bills contributed equally to this article.

⁵ J.L. Bills and S.X. Skapek, unpublished observation.

⁶ T.J. Triche, Children's Hospital Los Angeles, personal communication.

⁷ S.X. Skapek, unpublished observation.

Received 9/22/05; revised 2/14/06; accepted 3/15/06.

This article has been cited by other articles:

				L. Wang, J. Wang, B. W. Blaser, A.-M. Duchemin, D. F. Kusewitt, T. Liu, M. A. Caligiuri, and R. Briesewitz Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia Blood, September 15, 2007; 110(6): 2075 - 2083. [Abstract] [Full Text] [PDF]