Evodiamine is one of the major bioactive compounds that have been isolated and purified from the fruit of Evodiae fructus.
Evodiamine exhibits antitumor activities against the human
tumor cells, including multidrug-resistant
tumor cells. However, the molecular mechanism involved in cell death induced by
evodiamine treatment remains poorly understood. In the present study, we showed that
evodiamine activated the
caspase-dependent apoptotic pathway. This apoptosis was only partially inhibited by a pancaspase inhibitor
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl
ketone, which suggested that
evodiamine-induced apoptosis in leukemic U937 cells is partially
caspase independent. We observed the nuclear translocation of
apoptosis-inducing factor in
evodiamine-induced apoptosis of U937 cells, which may be responsible for the
caspase-independent apoptotic execution. We next showed that
evodiamine induced the substantial amount of apoptosis both in Bcl-2- and Akt-overexpressing U937 cells but not in human peripheral blood mononuclear cells. Although
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl
ketone inhibited
caspase activity in Bcl-2-overexpressing U937 cells, it completely prevented neither the induction of apoptosis or the nuclear translocation of
apoptosis-inducing factor, which suggests that
evodiamine is, at least in part, able to bypass the resistance of
leukemia cells via
caspase-independent apoptotic pathways. Thus, therapeutic strategy using
evodiamine may warrant further evaluation.