title: Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis.
abstract: Resting tumor cells represent a huge challenge during anticancer therapy due to their increased treatment resistance. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anticancer drug, currently in phases I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates. Here, we tested the ability of TRAIL to target cell cycle-arrested tumor cells. Cell cycle arrest was induced in tumor cell lines and xenografted tumor cells in G0, G1 or G2 using cytotoxic drugs, phase-specific inhibitors or RNA interference against cyclinB and E. Biochemical or molecular arrest at any point of the cell cycle increased TRAIL-induced apoptosis. Accordingly, when cell cycle arrest was disabled by addition of caffeine, the antitumor activity of TRAIL was reduced. Most important for clinical translation, tumor cells from three children with B precursor or T cell acute lymphoblastic leukemia showed increased TRAIL-induced apoptosis upon knockdown of either cyclinB or cyclinE, arresting the cell cycle in G2 or G1, respectively. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts enhanced antitumor activity against cell cycle-arrested tumor cells. Therefore, TRAIL might represent an interesting drug to treat static-tumor disease, for example, during minimal residual disease.
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrhardt
authors.forename: F
authors.initials: F
authors.lastname: Wachter
authors.forename: M
authors.initials: M
authors.lastname: Grunert
authors.forename: I
authors.initials: I
authors.lastname: Jeremias
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints; D059565:G2 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019926:Cyclin B; D019927:Cyclin E; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone; D004317:Doxorubicin; D008727:Methotrexate