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.

Gahlot, Satindra and Khan, Mohammad Aslam and Rishi, Loveena and Majumdar, Sekhar (2010) 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. Biochemical pharmacology, 80 (11). pp. 1650-61. ISSN 1873-2968

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Abstract

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.

Item Type: Article
Additional Information: Copyright of this article belongs to Elsevier Science
Uncontrolled Keywords: Apoptosis; Cutaneous T cell lymphoma; Pentoxifylline; Tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand
Subjects: Q Science > QD Chemistry
Depositing User: Dr. K.P.S.Sengar
Date Deposited: 08 Dec 2011 18:58
Last Modified: 08 Dec 2011 18:58
URI: http://crdd.osdd.net/open/id/eprint/499

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