A Farnesyltransferase Inhibitor Manumycin A Induces Oxidative DNA Damage and Apoptosis Via Oxidative Stress in Leukemia Cells.

Abstract

Farnesyltransferase inhibitors (FTIs) are currently under investigation for the treatment of leukemia. The mechanism of action of FTIs has not been clarified .In this study, we investigated the mechanism of actions of FTI manumycin in acute myeloid leukemia (AML) cells. We found that manumycin A (Manu) had an antineoplastic and apoptotic effect on leukemia cells. Manu significantly increased 8-OhdG, a reliable marker for assessment of oxidative DNA damage, formation. Manu also rapidly increased the phophorylation of H2AX in HL-60 and U937 cells. Methoxyamine, an inhibitor of base excision repair, enhanced the phophorylation of H2AX induced by Manu. Furthermore, Manu could induce phosphated p38 MAPK in HL-60 and U937 cells, and inhibitor of p38 MAPK could rescue leukemia cells from Manu-induced cytotoxicity. Moreover, Quenching of ROS with NAC prevented DNA damage, p38 phosphorylation and apoptosis by Manu. These results suggest the hierarchical position of ROS in oxidative DNA damage and apoptosis pathway. In conclusion, FTI induced oxidative DNA damage by induction of ROS and initiated the DNA damage responses then trigger the apoptosis involved p38 MAPK activation.