Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 405, Issue 2, Pages 314-318Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2011.01.036
Keywords
Fenretinide; Apoptosis; ROS; Ceramide; Acute myeloid leukemia
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Funding
- National Natural Science Foundation [30730033, 90919059, 30971623]
- Chinese Academy of Sciences [KSCX1-YW-22-01]
- Ministry of Science and Technology of China [2011CB910202, 2009CB825607]
- Shanghai Commission of Science and Technology [09410706500]
- European Community [200973]
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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 B-1 only in HL60 rather than the other two. Moreover, fumonisin B-1 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. (C) 2011 Elsevier Inc. All rights reserved.
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