Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis

Vinorelbine is a chemotherapeutic vinca alkaloid clinically prescribed for non-small cell lung cancer and breast cancer. Here we studied the mechanism for vinorelbine-induced apoptosis in a human T-cell lymphoma. Although vinorelbine induces DNA fragmentation that is inhibited by specific peptide in...

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Bibliographic Details
Published in:Apoptosis (London) 2008-04, Vol.13 (4), p.523-530
Main Authors: Hayakawa, Akemi, Kawamoto, Yoshiyuki, Nakajima, Hiroo, Sakai, Jun-ichi, Takasawa, Ryoko, Nakashima, Izumi, Magae, Junji, Tanuma, Sei-ichi
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
BH3 Interacting Domain Death Agonist Protein - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Caspase 3 - physiology
Caspase 8 - physiology
Caspase 9 - physiology
Cell Biology
Cell Line, Tumor
Cytochromes c - metabolism
Deoxyribonucleic acid
DNA
Humans
Jurkat Cells
Lung cancer
Lymphoma
Lymphoma, T-Cell - drug therapy
Lymphoma, T-Cell - pathology
Oncology
Original Paper
Vinblastine - analogs & derivatives
Vinblastine - pharmacology
Vinblastine - therapeutic use
Vinca
Virology
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Summary:Vinorelbine is a chemotherapeutic vinca alkaloid clinically prescribed for non-small cell lung cancer and breast cancer. Here we studied the mechanism for vinorelbine-induced apoptosis in a human T-cell lymphoma. Although vinorelbine induces DNA fragmentation that is inhibited by specific peptide inhibitors for caspases-9 and -3 in Jurkat cells, caspase-8 deficiency retards vinorelbine-induced apoptosis. Activation of caspase-8 is also observed in vinorelbine-treated cells, and the activity is diminished when the caspase-3 activity is blocked by a specific peptide inhibitor, Ac-DNLC-CHO. Blocking of the Fas receptor with an antagonistic anti-Fas antibody does not affect vinorelbine-induced DNA fragmentation. These results suggest that vinorelbine-induced apoptosis is enhanced by the activation of caspase-8 via caspase-9-mediated activation of caspase-3, but not through a Fas-triggered signal. Western blotting suggests that vinorelbine cleaves caspase-3, -9 and -8 and reduces the amount of mitochondrial cytochrome c. Caspase-8 deficiency suppresses all of these events. A downstream substrate for caspase-8, Bid, is also cleaved in vinorelbine-treated cells, but the Bid truncation is also observed in caspase-8-deficient Jurkat cells. Importantly, recombinant caspases-3 and -9, as well as caspase-8, directly cleaves recombinant Bid in vitro. These results suggest that caspases-3 and -9 participate in Bid truncation, indicating a new mechanism for vinorelbine-induces apoptosis.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-008-0184-y