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Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma.

Abstract：

OBJECTIVE:To investigate the mechanisms of antiproliferative effect induced by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in mantle cell lymphoma (MCL). MATERIALS AND METHODS:The antiproliferative effect of temsirolimus on three well-defined MCL cell lines was examined by the MTS assay. Induction of cell-cycle arrest, autophagy, and apoptosis were determined by fluorescence-activated cell sorting analysis. The molecular mechanisms underlining these effects were determined by Western blot. Synergy between temsirolimus and vorinostat were examined by MTS assay and the combination index was calculated. RESULTS:Temsirolimus has antiproliferative activity in three MCL cell lines in a dose- and time-dependent manner. Mechanistically, temsirolimus inhibited mTOR, as evidenced by inhibition of ribosomal S6 phosphorylation, and induced cell-cycle arrest in the G(0)/G(1) phase and a decrease in p21 expression without altering p27 or cyclin D1 levels. Furthermore, temsirolimus increased the number of acidic vesicular organelles and the amount of microtubule-associated protein 1 light-chain 3 processing, which are characteristic of autophagy, without induction of apoptosis. These changes were not associated with alteration in phosphorylated extracellular signal-regulated kinase (ERK), beclin-1, Bax, or Bak levels. In contrast, treatment of these cell lines with the histone deacetylase inhibitor vorinostat decreased ERK phosphorylation, activated caspase 3, and induced apoptosis. Moreover, temsirolimus synergized with submaximal concentrations of vorinostat in all MCL cell lines. CONCLUSION:This is the first report of temsirolimus-induced autophagy in MCL, and of vorinostat inhibition of ERK phosphorylation in MCL. Collectively, these data suggest that the combination of temsirolimus and vorinostat have synergistic antiproliferative activity in MCL cells by distinctively targeting apoptosis and autophagy.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Yazbeck VY,Buglio D,Georgakis GV,Li Y,Iwado E,Romaguera JE,Kondo S,Younes A

doi

10.1016/j.exphem.2007.12.008

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

443-50

issue

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(07)00705-9

journal_volume

pub_type

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Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma.