|
|
Induction of apoptosis in primary meningioma cultures by
fenretinide
Puduvalli VK, Li JT, Chen L, McCutcheon IE
Department of Neuro-Oncology and Neurosurgery, University of Texas M.D.
Anderson Cancer Center, Houston, Texas, USA. vpuduval@mdanderson.org
Fenretinide, a synthetic retinoid that induces apoptosis in tumor cells in
vitro, is being evaluated in clinical trials as a chemotherapeutic agent
against several malignancies.
Due to its ease of administration, long-term
tolerability, and low incidence of long-term side effects, we explored its
potential as a therapeutic agent against meningiomas by examining its
efficacy in vitro against such cells in primary culture.
Cells, cultured
from freshly resected benign, atypical, or malignant meningiomas, were
exposed to fenretinide (10 mumol/L).
Treatment effects were assessed using
flow cytometry, Western blot analysis, semiquantitative reverse
transcription-PCR for retinoid receptor expression, and changes in
insulin-like growth factor-I (IGF-I)-induced proliferation.
Fenretinide
induced apoptosis in the three grades of meningioma primary cells tested, as
shown by the appearance of a sub-G(1) fraction in flow cytometric analysis
and by the detection of poly-adenosyl ribonucleotidyl phosphorylase cleavage
indicating caspase activation.
Fenretinide treatment also increased levels
of the death receptor DR5 and caused mitochondrial membrane depolarization.
The levels of the retinoid receptors, retinoic acid receptor alpha and
retinoid X receptor gamma, were up-regulated in response to fenretinide,
suggestive of ligand-induced receptor up-regulation.
IGF-I-induced
proliferation in the meningioma cells was abolished by fenretinide.
We
conclude that fenretinide induces apoptosis in all three histologic subtypes
of meningioma and exerts diverse cellular effects, including DR5
up-regulation, modulation of retinoid receptor levels, and inhibition of
IGF-I-induced proliferation.
These results provide preliminary evidence that
fenretinide has activity against meningiomas and suggest that further
studies are warranted to explore its potential as a therapeutic agent
against meningiomas.
PMID: 15735044 [PubMed - in process]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15735044
|
