Leukemic cells responding to apoptosis-inducing drugs can be varied in terms of the mechanisms of action.
Fenretinide, a synthetic
retinoid, is worth of study as a promising candidate for apoptosis-based
therapy of
leukemia. Yet, it remains unclear whether this drug exerts the similar mechanisms on different leukemic cells. Here, we report a comparative analysis of
fenretinide-induced apoptosis in three acute myeloid leukemic (AML) cell lines including HL60, NB4 and U937. Through a series of antagonist assays, we revealed similarities and differences of mechanisms involved in these three cell lines.
Antioxidant vitamin C completely abrogated
fenretinide-induced apoptosis in all cell lines, demonstrating that ROS is an essential and common mediator. However, the apoptotic effects of
fenretinide could be blocked by
ceramide synthase inhibitor
fumonisin B1 only in HL60 rather than the other two. Moreover,
fumonisin B1 was unable to inhibit the generation of ROS in
fenretinide-treated HL60 cells, indicating that ROS may function as upstream stimulus of
ceramide-mediated apoptosis. These comparative results strongly suggest that the apoptotic response induced by
fenretinide in HL60 involves both ROS and
ceramide, whereas drug-induced apoptosis in NB4 and U937 requires ROS but is independent of
ceramide. Differentiated modes of action exerting on AML may guide the use of this apoptosis-inducing drug, and hence advance our knowledge about the nature of
cancer-specific responses to this drug.