LGP1, A Histone Deacetylase Inhibitor Analogue of FR235222, Sensitizes Promyelocytic Leukaemia U937 Cells to TRAIL-mediated Apoptosis

April 15, 2010

BlankLGP1, A Histone Deacetylase Inhibitor Analogue of FR235222, Sensitizes

Promyelocytic Leukaemia U937 Cells to TRAIL-mediated Apoptosis

1.. COSIMO WALTER D'ACUNTO1,

2.. ANNA CARRATÙ1,

3.. MANUELA RODRIQUEZ1,

4.. MAURIZIO TADDEI2,

5.. LUCA PARENTE1 and

6.. ANTONELLO PETRELLA1

+ Author Affiliations

1.. 1Department of Pharmaceutical Science, University of Salerno, Fisciano,

Salerno, Italy

2.. 2Department of Pharmaceutical Chemical Technology, Università of Siena,

Siena, Italy

1.. Correspondence to: Antonello Petrella, Ph.D., Department of Pharmaceutical

Science, University of Salerno, Via Ponte Don Melillo 84084 Fisciano (Salerno),

Italy. Tel: +39 089969762, Fax: +39 089969602, e-mail: apetrella@...

Abstract

Background: It has been shown that chemo-therapeutic agents, such as histone

deacetylase inhibitors (HDACi), are able to increase TRAIL-induced apoptosis in

many types of cancer. In the present study, we investigated the effects of the

novel HDACi LGP1, a new simplified analogue of FR235222, in human leukaemia U937

cells resistant to TRAIL-induced apoptosis. Materials and Methods: U937 cells

were incubated with TRAIL/LGP1 for 24 h and apoptosis was evaluated using flow

cytometric assay and cleavage of caspase-3 and (PARP) by Western blot. Western

blot analysis was also used to detect the expression of p21, p27, (NF-?, Bcl-2

and the levels of H4 histone acetylation. Finally, flow cytometry was used to

monitor the enhancement of TRAIL-receptor levels. Results: Treatment with LGP1

caused accumulation of acetylated histone H4 and G1 cycle arrest accompanied by

increase of p21. The compound was also able to sensitize U937 cells to

TRAIL-induced apoptosis through multiple mechanisms: (i) activation of caspase-3

and cleavage of PARP; (ii) induction of p21 and p27; (iii) cleavage of NF-?B and

down-regulation of Bcl-2. Finally, LGP1 induced up-regulation of TRAIL-R1

receptor expression.

Conclusion: These results demonstrate that U937 cells can be effectively killed

by a combination treatment of subtoxic doses of LGP1 and TRAIL.

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