Cisplatin-induced apoptosis by translocation of endogenous Bax in mouse collecting duct cells

Lee, RH Song, JM Park, MY Kang, SK Kim, YK Jung, JS

Rh. Lee et al., Cisplatin-induced apoptosis by translocation of endogenous Bax in mouse collecting duct cells, BIOCH PHARM, 62(8), 2001, pp. 1013-1023

60

INGLESE

Article

Pharmacology & Toxicology

BIOCHEMICAL PHARMACOLOGY

0006-2952 → ACNP

62

8

2001

1013 - 1023

ISI

0006-2952(20011015)62:8<1013:CABTOE>2.0.ZU;2-7

cis-Platinum(II) (cis-diammine dichloroplatinum; cisplatin) is a potent ant itumor compound that is widely used for the treatment of many malignancies. An important side-effect of cisplatin is nephrotoxicity, which results fro m injury to renal tubular epithelial cells and can be manifested as either acute renal failure or a chronic syndrome characterized by renal electrolyt e wasting. Recently, apoptosis has been recognized as an important mechanis m of cell death mediating the antitumor effect of cisplatin. This study was undertaken to examine the mechanisms of cell death induced by cisplatin in M-1 cells, which were derived from the outer cortical collecting duct cell s of SV40 transgenic mice. Treatment of M-1 cells with high concentrations of cisplatin (0.5 and 1 mM) for 2 hr led to necrotic cell death, whereas a 24-hr treatment with 5-20 muM cisplatin led to apoptosis. Antioxidants prot ected against cisplatin-induced necrosis, but not apoptosis, indicating tha t reactive oxygen species play a role in mediating necrosis but not apoptos is induced by cisplatin and that the mechanism of cell death induced by cis platin is concentration dependent. The low concentrations of cisplatin, whi ch induced apoptosis in M-1 cells, did not affect the expression levels of Bcl-2-related proteins and did not activate c-Jun NH2-terminal kinase (SAPK /JNK). Cisplatin induced the translocation of endogenous Bax from the cytos olic to the membrane fractions and, subsequently, the release of cytochrome c. Overexpression of Bcl-2 blocked cisplatin-induced apoptosis and Bax tra nslocation. These observations suggest that the subcellular redistribution of Bax is a critical event in the apoptosis induced by cisplatin. (C) 2001 Elsevier Science Inc. All rights reserved.