s-thalidomide has a greater effect on apoptosis than angiogenesis in a multiple myeloma cell line.

Abstract

s-Thalidomide has proven efficacy in multiple myeloma. Although it has both antiangiogenic and pro-apoptotic effects, its primary mode of therapeutic action remains unclear. We have investigated the changes to the expression of genes involved with these cellular processes following culture with s-thalidomide in the U266 MM cell line. Cells were cultured with s-thalidomide (0-1000 microM), and cell parameters, including apoptosis, were assessed on day 3. RNA was extracted from cells cultured for 24 h at the IC(50) concentration of s-thalidomide, and changes to gene expression were investigated by microarray methodologies. A reduction in cell viability was observed in U266 cells cultured with s-thalidomide (IC(50): 362 microM), which were mirrored by significant increases in apoptosis (for example, 200 microM on day 3: 40.3+/-3.1% vs. 3.2+/-0.4% on day 0; P<0.001). There were changes in the expression profile of genes involved in angiogenesis and apoptosis, but the changes were most dramatic in the apoptotic genes. In particular, the expression of I-kappaB kinase was decreased by two-fold, which was associated with a four-fold decrease in NF-kappaB expression. These data correlated with immunoblotting analyses, which showed significant increases in I-kappaB protein levels and decreased NF-kappaB activity. Additionally, the Bax : Bcl-2 ratio was significantly increased. Our data suggest that both angiogenic and apoptotic genes and proteins are affected by s-thalidomide. Additionally, a dramatic decrease in Bcl-2 expression with s-thalidomide suggests a possible enhancement of cytotoxic effect if combined with other cytotoxic agents.

• Authors: Wai M Liu, Sandra J Strauss, Tracy Chaplin, Sipra Shahin, David J Propper, Bryan D Young, Simon P Joel, James S Malpas
• Journal: The hematology journal : the official journal of the European Haematology Association (Hematol J) Vol. 5 Issue 3 Pg. 247-54 ( 2004) ISSN: 1466-4860 [Print] England
• PMID: 15167912 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• DNA, Neoplasm
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Thalidomide

Topics

• Angiogenesis Inhibitors (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA, Neoplasm (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Multiple Myeloma (pathology)
• NF-kappa B (metabolism)
• Neovascularization, Pathologic (prevention & control)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Thalidomide (pharmacology)