Enhancing effects of ceramide derivatives on 1,25-dihydroxyvitamin D(3)-induced differentiation of human HL-60 leukemia cells.
Differentiation-inducing therapy by agents such as 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] represents a useful approach for the treatment for cancer, including acute myeloid leukemia (AML). Recent studies demonstrated that the combined administration of 1,25-(OH)(2)D(3) and differentiation-enhancing agents could alleviate the side effects of 1,25-(OH)(2)D(3) and improve the rate of long term survival. In this study, we determined the enhancing activities of ceramide derivatives on 1,25-(OH)(2)D(3)-induced differentiation of human myeloid leukemia HL-60 cells. Importantly, some of these derivatives -- namely, A2, B3, and H9 -- enhanced the 1,25-(OH)(2)D(3)-induced differentiation of HL-60 cells in a concentration-dependent manner. In addition, the morphologic studies using Giemsa staining and flow cytometric analysis demonstrated that the combined treatment of 1,25-(OH)(2)D(3) with one of the three analogues, A2, B3, and H9, directed the HL-60 cells into monocytic lineage, but not into granulocytic lineage. The inhibition studies demonstrated that A2, B3, and H9, enhanced 1,25-(OH)(2)D(3)-induced differentiation of HL-60 cells via the PI3-K/PKC/JNK/ERK pathways. The ability of ceramide derivatives to enhance the differentiation-inducing potential of 1,25-(OH)(2)D(3) may contribute to an effective therapy for AML.
Kim
Dong Soo
DS
School of Life Sciences and Biotechnology, Korea University, Anam-Dong, Seoungbuk-Gu, Seoul, Republic of Korea.
Kim
Seung Hyun
SH
Song
Ju Han
JH
Chang
Young-Tae
YT
Hwang
Seung Yong
SY
Kim
Tae Sung
TS
D000954:Antigens, Surface / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002518:Ceramides / Q000138:chemical synthesis / Q000494:pharmacology*; D004357:Drug Synergism; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000737:chemistry / Q000166:cytology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D000954:Antigens, Surface; D000970:Antineoplastic Agents; D002518:Ceramides; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D020928:Mitogen-Activated Protein Kinases