Nargenicin enhances 1,25-dihydroxyvitamin D(3)- and all-trans retinoic acid-induced leukemia cell differentiation via PKCbetaI/MAPK pathways.
A major goal in the treatment of acute myeloid leukemia (AML) is to achieve terminal differentiation and prevent drug resistance and side effects. Combined treatment with low doses of ATRA or 1,25-(OH)(2)D(3) that do not induce toxicity with another drug is one useful strategy for the treatment of AML. Actinomycetes are the well known sources of antibiotics and bioactive molecules. Previously, we isolated nargenicin from the culture broth of an actinomycete isolate, Nocardia sp. CS682. In this study, we evaluated the effects of nargenicin on cellular differentiation in a human myeloid leukemia HL-60 cell system. Nargenicin inhibited cell proliferation and induced HL-60 cell differentiation when administered in combination with 1,25-(OH)(2)D(3) or ATRA. In addition, western blot analyses and kinase inhibitor studies demonstrated that nargenicin primarily enhanced leukemia cell differentiation via PKCbeta1/MAPK pathways. The results of this study indicate that nargenicin has the ability to induce differentiation and suggest that it may be useful for the treatment of neoplastic diseases.
School of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul 136-701, Republic of Korea.
Seung Hyun
SH
Kim
Jin Cheol
JC
Yoo
Tae Sung
TS
Kim
D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D064546:Protein Kinase C beta; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
D007783:Lactones; D014212:Tretinoin; C034624:nargenicin A1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate