Does caspase inhibition promote clonogenic tumor growth?
Defects in the control of cell death are a major cause of resistance to tumor therapy. Until recently, components of the intrinsic apoptotic pathway that act downstream of mitochondria, such as the caspases, have been apportioned only a minor share in this business. Thus, defects in mitochondrial caspase activation were suggested to cause apoptosis inhibition but not to confer clonogenic survival. This assumption was based on the finding that chemotherapeutic agents provoke mitochondrial damage even in the absence of caspases, resulting in the release of various toxic mediators and a subsequent caspase-independent cell death. In contrast to these earlier observations, we recently showed that in the absence of active caspases tumor cells do not necessarily undergo caspase-independent cell death but may even survive a chemotherapeutic insult. Our findings suggest that caspase inhibition can indeed promote clonogenic tumor growth which might be not only relevant for tumor therapy but should be also considered when evaluating the safety of therapeutic caspase inhibitors.
Fischer
Ute
U
Institute of Molecular Medicine, Heinrich-Heine-University, Düsseldorf, Germany. Ute.Fischer@uni-duesseldorf.de
Janssen
Katja
K
Schulze-Osthoff
Klaus
K
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010421:Pentanoic Acids / Q000494:pharmacology / Q000627:therapeutic use
C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D016588:Anticarcinogenic Agents; D061945:Caspase Inhibitors; D010421:Pentanoic Acids; D020169:Caspases