Cisplatin triggers apoptotic or nonapoptotic cell death in Fanconi anemia lymphoblasts in a concentration-dependent manner.
Cells derived from Fanconi anemia (FA) patients are hypersensitive for cross-linking agents, such as cisplatin, that are potent inducers of programmed cell death (PCD). Here, we studied cisplatin hypersensitivity in FA in relation to the mechanism of PCD in lymphoblastoid cells representing FA groups A and C. In FA cells, a low concentration of cisplatin caused chromatin condensation, phosphatidylserine (PS) externalization, and the expression of an 18-kDa variant of Bax, all indicators of apoptotic cell death, and the latter suggesting the involvement of a mitochondrial route. However, procaspases-3, -8, and -9, and PARP were not cleaved, although small increases in caspase activity could be detected. At a high concentration of cisplatin, both FA and corrected cells showed a robust cleavage of procaspases and PARP. DNA fragmentation was clearly visible under high cisplatin conditions and to some extent at a low concentration in FA-A cells, but not in the FA-C cell line regardless of the presence of functional FANCC, suggesting an unknown deficiency in these cells. We conclude that hypersensitivity in FA cells is associated with a mixture of necrotic and apoptotic features that is best described as apoptotic-like cell death, and that a defective FA pathway does not interfere with the proper activation of caspase-mediated cell death.
Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands.
Miriam
M
Ferrer
Thijs
T
Izeboud
Carlos G
CG
Ferreira
Simone W
SW
Span
Giuseppe
G
Giaccone
Frank A E
FA
Kruyt
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005199:Fanconi Anemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis; D010718:Phosphatidylserines / Q000378:metabolism; D011506:Proteins / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D003432:Cross-Linking Reagents; D010718:Phosphatidylserines; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020169:Caspases; D002945:Cisplatin