{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T17:32:03Z","timestamp":1783618323503,"version":"3.55.0"},"reference-count":110,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T00:00:00Z","timestamp":1393804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms15033746","type":"journal-article","created":{"date-parts":[[2014,3,3]],"date-time":"2014-03-03T11:27:10Z","timestamp":1393846030000},"page":"3746-3767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Killing Me Softly\u2014Future Challenges in Apoptosis Research"],"prefix":"10.3390","volume":"15","author":[{"given":"Mike-Andrew","family":"Westhoff","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Br\u00fchl","sequence":"additional","affiliation":[{"name":"Laboratorio Analisi Sicilia Catania, Lentini (SR) 96016, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Nonnenmacher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Karpel-Massler","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medical Center Ulm, Ulm 89081, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Michael","family":"Debatin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.immuni.2013.02.003","article-title":"Necroptosis: The release of damage-associated molecular patterns and its physiological relevance","volume":"38","author":"Kaczmarek","year":"2013","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1172\/JCI26390","article-title":"Autophagy in cell death: An innocent convict?","volume":"115","author":"Levine","year":"2005","journal-title":"J. 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