A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins.

Abstract	Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.
Authors	J Blake Marriott, Ian A Clarke, Anna Czajka, Keith Dredge, Kay Childs, Hon-Wah Man, Peter Schafer, Sowmya Govinda, George W Muller, David I Stirling, Angus G Dalgleish
Journal	Cancer research (Cancer Res) Vol. 63 Issue 3 Pg. 593-9 (Feb 01 2003) ISSN: 0008-5472 [Print] United States
PMID	12566301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents BAK1 protein, human Bak1 protein, mouse Bax protein, mouse Caspase Inhibitors Membrane Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 SelCID-3 bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein Thalidomide Cyclic AMP CASP3 protein, human Casp3 protein, mouse Caspase 3 Caspases
Topics	Animals Antineoplastic Agents (pharmacology) Apoptosis (drug effects, physiology) Caspase 3 Caspase Inhibitors Caspases (metabolism, physiology) Cell Cycle (drug effects) Cell Division (drug effects) Colorectal Neoplasms (drug therapy, metabolism, pathology) Cyclic AMP (biosynthesis) Female Humans Male Melanoma (drug therapy, metabolism, pathology) Membrane Proteins (biosynthesis) Mice Mice, Nude Pancreatic Neoplasms (drug therapy, metabolism, pathology) Prostatic Neoplasms (drug therapy, metabolism, pathology) Proto-Oncogene Proteins (biosynthesis) Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, physiology) Thalidomide (analogs & derivatives, pharmacology) Tumor Cells, Cultured Xenograft Model Antitumor Assays bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein

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