Author : Ghada Mahmoud Abou-Lteif
Publisher :
Page : 176 pages
File Size : 49,72 MB
Release : 2008
Category :
ISBN :
N-(4-hydroxyphenyl)retinamide (HPR) is a synthetic retinoid that inhibits growth and induces apoptosis in many human cell lines including those that are resista nt to natural retinoids. Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell malignancy caused by human T-cell lymphotropic virus type I (H TLV-I). ATL carries a poor prognosis with a mean survival time of less than eig ht months, in the acute form, mainly due to acquired resistance to chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I-induced t ransformation and apoptosis resistance. We have previously shown that HPR inhibits proliferation and induces apoptosis i n all tested ATL and HTLV-I-negative malignant T cell lines, while no effect is observed on normal lymphocytes (Darwiche 2004). The mechanisms of HPR-induced c ell death are complex and involve signaling pathways mediated by free radicals o r reactive oxygen species (ROS). Using ATL as a model, we aim at deciphering th e mechanisms generating ROS and apoptosis of malignant T cells in response to HP R. We will explore the involvement of ROS in HPR-induced apoptosis, the contrib ution of the different biochemical pathways of ROS generation in relation to HPR -induced cell death; and Tax modulation of HPR induced ROS accumulation and ROS- induced cell death. We identified HPR-induced ROS generation as the key mediator of cell cycle arres t and apoptosis of malignant T cells. Pre-treatment with antioxidants inhibited ROS generation, prevented HPR-induced ceramide accumulation, cell cycle arrest, cytochrome c release, caspase-activation and apoptosis. The expression of the HTLV-I oncoprotein Tax abrogated HPR-induced ROS accumulation in HTLV-I-infected cells, which explains their lower sensitivity to HPR. Of the enzyme systems fr equently implicated in ROS generation, only phospholipase A2 (PLA2) and lipooxyg enase (LOX) were shown to be involved in ROS generation and growth suppression i n response to HPR in HTLV-I-negative malignant T cells Defining the mechanism of free radical induction by HPR may support a potential therapeutic role for this synthetic retinoid in ATL and HTLV-I-negative T-cell l ymphomas.