Caspase inhibition switches doxorubicin-induced apoptosis to senescence.
The inhibition of apoptosis is generally believed to be a major determinant of resistance to chemotherapy. However, recent findings have shown that caspase inhibitors do not protect cancer cells from death by cytotoxic agents, but may switch drug-induced apoptosis to an alternative 'default death'. The primary goals of this study were to determine the major characteristics of the 'default death' and the mechanism by which this switch is activated. For this purpose, we first investigated putative cell death modes induced by doxorubicin. Molecular markers associated with these death modes were utilized to identify the default death resulting from the inhibition of apoptosis. Our findings demonstrated that doxorubicin induced at least three distinct types of cell death, senescence, apoptosis and a type of necrosis, which were concentration dependent. Specific molecular markers such as p21/WAF1, activated caspase-3 and activated Akt were associated with these death modes. The pan-caspase inhibitor (Q-VD-OPH) greatly reduced doxorubicin-induced caspase-3 activation but did not protect cells against drug toxicity. The combination of doxorubicin and Q-VD-OPH caused an increased expression of p21/WAF1 and senescence -associated -beta-galactosidase activity, but did not alter Akt activation. Collectively, these findings suggest that the inhibition of apoptosis may lead to an increased expression of cell cycle inhibitors and cellular senescence.
Department of Pediatrics, Children's Memorial Institute for Education and Research, M/C 224 Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614, USA. arebbaa@childrensmemorial.org
Abdelhadi
A
Rebbaa
Xin
X
Zheng
Pauline M
PM
Chou
Bernard L
BL
Mirkin
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001932:Brain Neoplasms; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D004317:Doxorubicin