Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.
Sci Rep
; 5: 16488, 2015 Nov 18.
Article
em En
| MEDLINE
| ID: mdl-26576726
ABSTRACT
Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer.
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Base de dados:
MEDLINE
Assunto principal:
Apoptose
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Apoptossomas
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Células Intersticiais do Testículo
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Mercaptopurina
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Antimetabólitos Antineoplásicos
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article