RRC ID 12223
Author Numazawa S, Inoue N, Nakura H, Sugiyama T, Fujino E, Shinoki M, Yoshida T, Kuroiwa Y.
Title A cardiotonic steroid bufalin-induced differentiation of THP-1 cells. Involvement of Na+, K(+)-ATPase inhibition in the early changes in proto-oncogene expression.
Journal Biochem Pharmacol
Abstract Human monocytic leukemia THP-1 cells were induced to differentiate into macrophage-like cells by treatment with cardiotonic steroid bufalin, which was previously shown to interact with the Na+, K+-ATPase with similar kinetics to ouabain, a specific inhibitor of the enzyme. This induction of differentiation was characterized by loss of proliferation, cell adherence, increased ability to reduce Nitro Blue tetrazolium (NBT), and increased expression of interleukin 1 beta (IL-1 beta). During this process, bufalin downregulated c-myb and c-myc expressions and induced c-fos and Egr-1 transcripts. Ouabain also caused similar changes in proto- oncogene expression and induced phenotypic markers of differentiated cells at concentrations comparable to bufalin. The 12-O-tetradecanoyl phorbol-13-acetate resistant THP-1 cell variant, which was unresponsive to this agent as to growth inhibition and proto-oncogene expression, responded to bufalin. The finding that protein kinase inhibitor H7 failed to bufalin-mediated c-fos induction further supports the theory that the signal transduction machinery caused by bufalin is separable from the phorbol ester. The cytotoxic effect of high doses of bufalin apparently disappeared in the medium where Na+ was replaced with choline ions. Furthermore, bufalin failed to induce c-fos expression and to downregulate c-myb transcripts in the low-Na+ medium. These findings indicate that an increased intracellular Na+ concentration resulting from the Na+, K(+)-ATPase inhibition possibly triggers the change in proto-oncogene expression evoked by bufalin.
Volume 52(2)
Pages 321-9
Published 1996-7-26
DOI 10.1016/0006-2952(96)00210-9
PII 0006295296002109
PMID 8694857
MeSH Bufanolides / pharmacology* Cardiotonic Agents / pharmacology* Cell Differentiation / drug effects* Gene Expression Regulation / drug effects Humans Leukemia, Myeloid Proto-Oncogene Proteins / metabolism* Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors* Tetradecanoylphorbol Acetate / pharmacology Tumor Cells, Cultured / drug effects
IF 4.825
Times Cited 29
DNA material P450 1A2 (CYP1A2) cDNA (RDB01244) P450 2B1 (CYP2B1) cDNA (RDB01245)