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TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window.
Koschny, Ronald; Ganten, Tom M; Sykora, Jaromir; Haas, Tobias L; Sprick, Martin R; Kolb, Armin; Stremmel, Wolfgang; Walczak, Henning.
Afiliación
  • Koschny R; Division of Apoptosis Regulation, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hepatology ; 45(3): 649-58, 2007 Mar.
Article en En | MEDLINE | ID: mdl-17326159
UNLABELLED: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the synergistic antitumor effect of bortezomib in combination with TRAIL in hepatoma, colon, and pancreatic cancer cells in comparison to the toxicity in primary human hepatocytes (PHH). TRAIL cotreatment at high but clinically relevant concentrations of bortezomib caused toxicity in PHH which potentially limits the clinical applicability of bortezomib/TRAIL cotreatment. However, at low concentrations of bortezomib TRAIL-resistant hepatoma, colon and pancreatic cancer cell lines but not PHH were efficiently sensitized for TRAIL-induced apoptosis. RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIPL down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL. Bim, although accumulated upon bortezomib treatment, did not play a causal role for TRAIL sensitization in Hep3b cells. Combined treatment with bortezomib and TRAIL massively reduced the clonogenic capacity of hepatoma cells in vitro. Surviving clones could be resensitized for repeated TRAIL treatment. CONCLUSION: Bortezomib/TRAIL cotreatment bears the risk of severe hepatotoxicity at high but clinically relevant concentrations of bortezomib. However, within a wide therapeutic window bortezomib sensitized different cancer cells but not PHH for TRAIL-induced apoptosis.
Asunto(s)
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazinas / Ácidos Borónicos / Apoptosis / Ligando Inductor de Apoptosis Relacionado con TNF / Hígado / Antineoplásicos Límite: Humans Idioma: En Revista: Hepatology Año: 2007 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazinas / Ácidos Borónicos / Apoptosis / Ligando Inductor de Apoptosis Relacionado con TNF / Hígado / Antineoplásicos Límite: Humans Idioma: En Revista: Hepatology Año: 2007 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos