15645129

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2

Our previous studies demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) had pharmacological activity for the treatment of myeloid leukemia patients. In the present study, we investigated the effects of TPA alone or in combination with capsaicin (8-methyl-N-vanillyl-6-nonenamide) on growth and differentiation in myeloid leukemia HL-60 cells and in a TPA-resistant HL-60 variant cell line termed HL-525. Treatment of HL-60 cells with TPA (0.16-1.6 nM) for 48 h resulted in concentration-dependent growth inhibition and cell differentiation (via the macrophage pathway). Capsaicin (5-50 microM) inhibited the growth of HL-60 cells in a concentration-dependent manner. Treatment of HL-60 cells with capsaicin alone only resulted in a small increase in the number of differentiated cells but treatment of the cells with TPA in combination with capsaicin synergistically increased differentiation. Moreover, inhibitors of protein kinase C (PKC), 7-hydroxystaurosporin (UCN-01; 100 nM) and chelerythrine (0.5 microM), significantly decreased HL-60 cell differentiation induced by the combination of TPA and capsaicin. These results suggest that PKC may be involved in HL-60 cell differentiation induced by TPA in combination with capsaicin. Capsaicin alone caused a very small increase in differentiation in the TPA-resistant HL-525 cells. However, treatment of HL-525 cells with combinations of TPA (0.16 nM) and capsaicin (10-50 microM) caused a strong synergistic increase in differentiation. Results from the present study suggest that a combination of TPA and capsaicin may improve the therapeutic efficacy of TPA and overcome resistance to TPA in some myeloid leukemia patients.

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1019-6439

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441-8

pubmed-meshheading:15645129-Alkaloids, pubmed-meshheading:15645129-Antineoplastic Agents, pubmed-meshheading:15645129-Benzophenanthridines, pubmed-meshheading:15645129-Capsaicin, pubmed-meshheading:15645129-Carboxylesterase, pubmed-meshheading:15645129-Carcinogens, pubmed-meshheading:15645129-Cell Adhesion, pubmed-meshheading:15645129-Cell Differentiation, pubmed-meshheading:15645129-Cell Line, Tumor, pubmed-meshheading:15645129-Cell Survival, pubmed-meshheading:15645129-Dose-Response Relationship, Drug, pubmed-meshheading:15645129-Enzyme Inhibitors, pubmed-meshheading:15645129-HL-60 Cells, pubmed-meshheading:15645129-Humans, pubmed-meshheading:15645129-Leukemia, Myeloid, pubmed-meshheading:15645129-Macrophages, pubmed-meshheading:15645129-Models, Chemical, pubmed-meshheading:15645129-Phenanthridines, pubmed-meshheading:15645129-Protein Kinase C, pubmed-meshheading:15645129-Staurosporine, pubmed-meshheading:15645129-Tetradecanoylphorbol Acetate, pubmed-meshheading:15645129-Time Factors

Synergistic stimulatory effect of 12-O-tetradecanoylphorbol-13-acetate and capsaicin on macrophage differentiation in HL-60 and HL-525 human myeloid leukemia cells.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural