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.
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.
Gahlot
Satindra
S
Division of Cell Biology and Immunology, Institute of Microbial Technology (CSIR), Chandigarh 160036, India.
Khan
Mohammad Aslam
MA
Rishi
Loveena
L
Majumdar
Sekhar
S
D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000502:physiology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism / Q000473:pathology*; D010431:Pentoxifylline / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000096:biosynthesis* / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
D000277:Adjuvants, Pharmaceutic; D051017:Apoptosis Regulatory Proteins; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D010431:Pentoxifylline