title: Killing me softly--future challenges in apoptosis research.
abstract: The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the complexity of combination therapy is elucidated using the PI3-K-mediated signaling network as a specific example. Here we show that the current clinical approach to sensitize malignancies to apoptosis by maximal, prolonged inhibition of so-called survival pathways can actually be counter productive. Third, we propose that under certain conditions which will need to be clearly defined in future, chronification of a tumor might be preferable to the attempt at a cure. Finally, we discuss further problems with utilizing apoptosis induction in cancer therapy and propose a novel potential therapeutic approach that combines the previously discussed features.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany. andrew.westhoff@uniklinik-ulm.de.
authors.forename: Mike-Andrew
authors.initials: MA
authors.lastname: Westhoff
authors.affiliation: Laboratorio Analisi Sicilia Catania, Lentini (SR) 96016, Italy. kontakt@oliverbruehl.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brühl
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany. lisa.nonnenmacher@uniklinik-ulm.de.
authors.forename: Lisa
authors.initials: L
authors.lastname: Nonnenmacher
authors.affiliation: Department of Neurosurgery, University Medical Center Ulm, Ulm 89081, Germany. georg.karpel@uniklinik-ulm.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany. klaus-michael.debatin@uniklinik-ulm.de.
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D059248:Chemoradiotherapy; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases