Suppression of mitochondrial permeability transition pore and induction of lymphoma P388 cell death by cyclosporin A

Suppression of the mitochondrial permeability transition pore (PTP) and induction of lymphoma P388 cell death were studied in the presence of cyclosporin A (CsA) and its derivatives. In experiments with permeabilized P388 cells, CsA and its nonimmunosuppressive derivative N-methyl-Val-4-CsA, but not cyclosporin H (CsH), enhanced Ca2+ accumulation in mitochondria and suppressed PTP opening. Moreover, CsA was able either itself to induce or to enhance a prooxidant-induced P388 programmed cell death. Blebbing and formation of apoptotic bodies were among the observed CsA effects. N-Methyl-Val-4-CsA showed similar effects, but CsH had no effect on P388 cell death. These results show that initial-stage P388 tumour cell death is not related to PTP opening but can be the result of PTP closing with a corresponding increase in the formation of reactive oxygen species.