c-Jun-NH2-terminal kinase potentiates apoptotic cell death in response to carboplatin in B lymphoma cells.

Abstract

PURPOSE:

Exposure to carboplatin (CBDCA) has been demonstrated to result in apoptotic and/or necrotic cell death, but molecular mechanisms underlying CBDCA-induced apoptosis or necrosis remain largely unclear. Here, we examined whether activation of c-Jun NH(2)-terminal kinase (JNK) modulates the mode of cell death induced by CBDCA in CD31 B lymphoma cells.

METHODS:

The mode of cell death (apoptosis versus necrosis) was investigated by flow cytometry using 7-amino-actinomycin D (7-AAD) and annexin-FITC probes. To evaluate the role of JNK1 in CBDCA-induced cell death, CH31 B lymphoma cells overexpressing dominant-negative form of JNK1 (dnJNK1) or constitutively active form of JNK1 (MKK7-JNK1) were established. Intracellular accumulation of superoxide anion (O(2) (-)) was determined by flow cytometry using the fluorescent probe dihydroethidium (DHE).

RESULTS:

The CBDCA-induced primary apoptosis and secondary necrosis were abrogated in the dnJNK1-overexpressing CH31 cells, while it was somewhat enhanced in the MKK7-JNK1-overexpressing cells. In contrast, the CBDCA-induced primary necrosis was reduced by MKK7-JNK1, with a concurrent decrease in production of O(2) (-). The superoxide anion scavenger for butylated hydroxyanisol (BHA) partially reduced the CBDCA-induced O(2) (-) production and necrotic, but not apoptotic, death in both wild type and dnJNK1-overexpressing CH31 cells.

CONCLUSIONS:

Prolonged activation of JNK1 appears to be involved in CBDCA-induced apoptosis with prevention of necrosis induction, and the induction of necrosis appears to correlate with CBDCA-induced O(2) (-) production, which is partially blocked by co-culture with BHA. These observations provide valuable information for understanding molecular mechanisms underlying CBDCA-induced cell death, and hopefully for the design of novel treatment modalities for patients with tumors.

• Authors: Eiko Takada, Kikumi Hata, Junichiro Mizuguchi
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 4 Pg. 569-76 (Sep 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 18026729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Superoxides
• Butylated Hydroxyanisole
• Carboplatin
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 7

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Butylated Hydroxyanisole (pharmacology)
• Carboplatin (pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Antagonism
• Enzyme Activation (drug effects)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lymphoma, B-Cell (drug therapy, enzymology, pathology)
• MAP Kinase Kinase 7 (metabolism)
• Mice
• Necrosis (chemically induced)
• Superoxides (metabolism)