title: Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells.
authors: Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors: Jan
authors: J
authors: Molinsky
authors: Magdalena
authors: M
authors: Klanova
authors: Michal
authors: M
authors: Koc
authors: Lenka
authors: L
authors: Beranova
authors: Ladislav
authors: L
authors: Andera
authors: Zdenka
authors: Z
authors: Ludvikova
authors: Martina
authors: M
authors: Bohmova
authors: Zdenka
authors: Z
authors: Gasova
authors: Miroslav
authors: M
authors: Strnad
authors: Robert
authors: R
authors: Ivanek
authors: Marek
authors: M
authors: Trneny
authors: Emanuel
authors: E
authors: Necas
authors: Jan
authors: J
authors: Zivny
authors: Pavel
authors: P
authors: Klener
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D053222:Fas Ligand Protein / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D014176:Protein Biosynthesis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053222:Fas Ligand Protein; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011687:Purines; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D000077546:Roscovitine