Antineoplasic agents such as cisplatin and adriamycin execute their pharmacological role by triggering apoptosis. We have studied the mechanism of apoptosis induction by cisplatin and adriamycin. Both drugs activated JNK with slow and persistent kinetics. Adriamycin activated caspase-3 before the rise in JNK activity, while the response to cisplatin occurs hours after JNK activation. The increase in JNK activity was necessary for cisplatin-mediated apoptosis but it was dispensable for adriamycin-induced cell death. Cells derived from c-jun knock out mice were more resistant to cisplatin cell death than normal cells, but no difference was observed in response to adriamycin. Activation of JNK and cell death by cisplatin is mediated by the MEKK1/SEK1 cascade, since expression of dominant negative expression vectors of these kinases blocked both processes. p38 was also activated by cisplatin with similar kinetics as JNK. AP-1 complexes were activated by cisplatin including mainly c-jun/ATF-2 heterodimers suggesting that AP-1-dependent transcription partially mediated cisplatin-induced apoptosis.
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