bryostatin-5 and Leukemia--Myeloid--Acute

We examined the effect of bryostatin-5 (bryo-5) with and without a combination of myeloid growth promoting factors on human acute myeloid leukemia (AML) cell growth, maturation, and primary plating efficiency. In vitro treatment of AML samples with bryo-5 induced a macrophage-like cell differentiation as evidenced by morphological changes, esterase staining, and cell surface expression of CD11a and CD18. AML cells exposed to growth factors doubled their cell numbers following culture, this increase being abrogated by co-exposure to bryo-5. An antiproliferative effect, as well as the antagonistic interaction of bryo-5 with growth factors, was confirmed in methylcellulose clonogenic assays. Together, these findings indicate that the compound bryo-5 exerts an anti-proliferative effect on AML cells and counteracts growth factor induced leukemic proliferation.

Topics: Adult; Aged; Antigens, CD; Antineoplastic Agents; Bryostatins; Cell Differentiation; Cell Division; Cell Survival; Clone Cells; Enzyme Activation; Female; Growth Substances; Humans; Integrins; Lactones; Leukemia, Myeloid, Acute; Macrolides; Macrophages; Male; Middle Aged; Protein Kinase C; Tumor Cells, Cultured

Bryostatin 5 is a macrocyclic lactone which activates protein kinase C (PKC). PKC activation has been implicated in leukemic cell differentiation. We have examined the effect of PKC activation by bryostatin 5 on human acute myeloid cell differentiation in the presence and absence of vitamin D3. In vitro treatment of 20 patient samples of acute myeloid leukemias in a 4 days culture system with 10 nM bryostatin 5 induced strongly adherent macrophage-like cells in all cases. Bryostatin 5 induced a significant (p = 0.00006) increment in esterase activity in a majority of the samples, which was further enhanced by vitamin D3. CD14 expression was significantly (p = 0.035) enhanced with the combination of bryostatin 5 and vitamin D3. Nitroblue tetrazolium (NBT) reducing ability was, however, nearly abolished (p = 0.0007). A loss of CD34 expression occurred during cell culture; this loss was enhanced by vitamin D3, but prevented partly by bryostatin 5. Together these findings indicate that exposure to bryostatin 5 leads to a strong macrophage-like cell differentiation in human myeloid leukemia and that VD3 has an additional effect. These findings strengthen the potential role of bryostatins as possible antileukemic agents.

Topics: Adolescent; Adult; Aged; Antigens, CD; Antigens, CD34; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Bryostatins; Carboxylic Ester Hydrolases; Cell Differentiation; Cholecalciferol; Drug Synergism; Enzyme Activation; Female; Humans; Lactones; Leukemia, Myeloid, Acute; Lipopolysaccharide Receptors; Macrolides; Macrophages; Male; Middle Aged; Protein Kinase C; Tumor Cells, Cultured