Pramanicin is a novel anti-fungal
drug with a wide range of potential application against human diseases. It has been previously shown that
pramanicin induces cell death and increases
calcium levels in vascular endothelial cells. In the present study, we showed that
pramanicin induced apoptosis in Jurkat T
leukemia cells in a dose- and time-dependent manner. Our data reveal that
pramanicin induced the release of
cytochrome c and
caspase-9 and
caspase-3 activation, as evidenced by detection of active
caspase fragments and fluorometric
caspase assays.
Pramanicin also activated
c-jun N-terminal kinase (JNK), p38 and
extracellular signal-regulated kinases (ERK 1/2) with different time and dose kinetics. Treatment of cells with specific MAP
kinase and
caspase inhibitors further confirmed the mechanistic involvement of these signalling cascades in
pramanicin-induced apoptosis. JNK and p38 pathways acted as pro-apoptotic signalling pathways in
pramanicin-induced apoptosis, in which they regulated release of
cytochrome c and
caspase activation. In contrast the ERK 1/2 pathway exerted a protective effect through inhibition of
cytochrome c leakage from mitochondria and
caspase activation, which were only observed when lower concentrations of
pramanicin were used as apoptosis-inducing agent and which were masked by the intense apoptosis induction by higher concentrations of
pramanicin. These results suggest
pramanicin as a potential apoptosis-inducing small molecule, which acts through a well-defined JNK- and p38-dependent apoptosis signalling pathway in Jurkat T
leukemia cells.