Pentoxifylline augments TRAIL/Apo2L mediated apoptosis in cutaneous T cell lymphoma (HuT-78 and MyLa) by modulating the expression of antiapoptotic proteins and death receptors.
Biochem Pharmacol
; 80(11): 1650-61, 2010 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-20804743
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising anticancer agent but cutaneous T lymphoma cells (CTCL) are less sensitive to TRAIL-induced apoptosis. Here, we report that pentoxifylline (PTX), a phosphodiesterase inhibitor, augments TRAIL-mediated apoptosis in HuT-78 and MyLa cells through modulating extrinsic death receptors and intrinsic mitochondria dependent pathways. Our results clearly show that PTX augments TRAIL-mediated activation of caspase-8 and induces cleavage of Bid, although PTX alone cannot activate caspase-8. This is followed by cytochrome c release and subsequent, activation of caspase-9 and caspase-3 and cleavage of poly (ADP ribose) polymerase (PARP). Combined treatment downregulates the expression of various antiapoptotic proteins including c-FLIP, Bcl-xl, cIAP-1, cIAP-2 and XIAP. PTX induces the expression of death receptors DR4 and DR5 on cell surface of both the cell types where c-Jun NH2-terminal kinase (JNK) pathway plays an important role. Moreover, combined silencing of DR4 and DR5 by small interfering RNA abrogates the ability of PTX to induce TRAIL-mediated apoptosis. Thus, this is the first demonstration that PTX can potentiate TRAIL-mediated apoptosis through downregulation of cell survival gene products and upregulation of death receptors.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Pentoxifilina
/
Regulação Neoplásica da Expressão Gênica
/
Adjuvantes Farmacêuticos
/
Linfoma Cutâneo de Células T
/
Apoptose
/
Proteínas Reguladoras de Apoptose
/
Ligante Indutor de Apoptose Relacionado a TNF
/
Receptores de Morte Celular
Limite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Índia