cotylenin-a and Leukemia--Myeloid

Acute myeloid leukemia (AML) is characterized by the arrest of differentiation leading to the accumulation of immature cells. This maturation arrest can be reversed by certain agents. Although differentiation therapy for patients with acute promyelocytic leukemia (APL) using all-trans retinoic acid (ATRA) has been established, the clinical response of AML patients other than those with APL to ATRA is limited. We must consider novel therapeutic drugs against other forms of AML for the development of a differentiation therapy for leukemia. Regulators that play an important role in the differentiation and development of plants or invertebrates may also affect the differentiation of human leukemia cells through a common signal transduction system, and might be clinically useful for treating AML. Cotylenin A, a plant growth regulator, is a potent and novel inducer of the monocytic differentiation of human myeloid leukemia cell lines and leukemia cells freshly isolated from AML patients.

Topics: Animals; Antigens, Differentiation; Antineoplastic Agents, Phytogenic; Cell Differentiation; Cholecalciferol; Diterpenes; Drug Screening Assays, Antitumor; Drug Synergism; HL-60 Cells; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Mice; Neoplastic Stem Cells; Retinoids; Structure-Activity Relationship; Tretinoin; Tumor Cells, Cultured

Cytokinins are important purine derivatives that act as redifferentiation-inducing hormones to control many processes in plants. Cytokinins such as isopentenyladenine (IPA) and kinetin are very effective at inducing the granulocytic differentiation of human myeloid leukemia HL-60 cells. We examined the gene expression profiles associated with exposure to IPA using cDNA microarrays and compared the results with those obtained with other inducers of differentiation, such as all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 (VD3) and cotylenin A (CN-A). Many genes were up-regulated, and only a small fraction were down-regulated, upon exposure to the inducers. IPA and CN-A, but not ATRA or VD3, immediately induced the expression of mRNA for the calcium-binding protein S100P. The up-regulation of S100P was confirmed at the protein expression level. We also examined the expression of other S100 proteins, including S100A8, S100A9 and S100A12, and found that IPA preferentially up-regulated S100P at the early stages of differentiation. IPA-induced differentiation of HL-60 cells was suppressed by treatment with antisense oligonucleotides against S100P, suggesting that S100P plays an important role in cell differentiation.

Topics: Adenine; Calcitriol; Calcium-Binding Proteins; Cell Differentiation; Cell Line, Tumor; Cytokinins; Diterpenes; DNA, Complementary; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Isopentenyladenosine; Leukemia, Myeloid; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Tretinoin; U937 Cells; Up-Regulation

Regulators that play an important role in the differentiation and development of plants or invertebrates may also affect the differentiation of human leukaemia cells through a common signal transduction system, and might be clinically useful for treating acute myeloid leukaemia. Cotylenin A has been isolated as a plant growth regulator. We examined the effects of cotylenin A on the differentiation of several myelogenous leukaemia cells, and found that cotylenin A is a potent and novel inducer of the monocytic differentiation of human myeloid leukaemia cells. Cotylenin A induced the functional and morphological differentiation of myeloblastic and promyelocytic leukaemia cells, but did not effectively induce the differentiation of monocytoid leukaemia cells. Cotylenin A-induced differentiation was not affected by several inhibitors of signal transduction, suggesting that this inducer exhibits a unique mode of action.

Topics: Androstadienes; Antineoplastic Agents; Biomarkers; Cell Differentiation; Diterpenes; Enzyme Inhibitors; Flavonoids; HL-60 Cells; Humans; Indoles; Interferon-gamma; Leukemia, Myeloid; Lipopolysaccharide Receptors; Maleimides; Monocytes; Naphthalenes; Plant Growth Regulators; Tretinoin; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; U937 Cells; Virulence Factors, Bordetella; Wortmannin

Cotylenin A, which has a diterpenoid tricarbocyclic skeleton, has been isolated as a plant growth regulator, has been shown to affect several physiological processes of higher plants and have differentiation-inducing activity in several myeloid leukaemia cell lines. We examined the effect of cotylenin A on the differentiation of leukaemic cells that were freshly isolated from acute myeloid leukaemia (AML) patients in primary culture. Cotylenin A significantly stimulated both functional and morphological differentiation of leukaemia cells in 9 out of 12 cases. This differentiation-inducing activity was more potent than those of all-trans retinoic acid and 1alpha,25-dihydroxyvitamin D3 (VD3). Treatment with a combination of cotylenin A and VD3 was more effective than cotylenin A or VD3 alone at inducing the monocytic differentiation of AML cells.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Calcitriol; Cell Differentiation; Diterpenes; Drug Synergism; Female; Humans; Lectins, C-Type; Leukemia, Myeloid; Lipopolysaccharide Receptors; Macrophage-1 Antigen; Male; Middle Aged; Plant Growth Regulators; Statistics, Nonparametric; Tretinoin; Tumor Cells, Cultured

Protein factors playing a significant part in differentiation and development have been recently elucidated. However, low molecular factors which also seem to be essential remain still unknown, although only retinoic acid has become such a candidate. Cotylenins had been isolated as the plant-growth regulators, and have been found to affect a number of physiological processes of higher plants. Here we report that at the concentrations above 12.5 microg/ml (20 microM) cotylenin A induced the functional and morphological differentiation in murine (M1) and human myeloid leukemia (HL-60) cells. Although cotylenin A has some similarity to PMA both in carbotricyclic diterpene structure and in biological activity (i.e. differentiation-induction of HL-60 cells into macrophages), the activation of PKC and the elevation of Ca2+-levels by cotylenin A were not observed. Quite recently it has been reported that fusicoccin (closely related to cotylenin A)-targets are 14-3-3 proteins, which are at the crosspoint of a huge array of signalling and regulatory pathways. These results suggest that cotylenin A might become a useful tool for the elucidation of molecular mechanisms of differentiation and development.

Topics: Animals; Calcium; Cell Differentiation; Cladosporium; Diterpenes; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Induction; Growth Inhibitors; HL-60 Cells; Humans; Intracellular Fluid; Leukemia, Myeloid; Mice; Muramidase; Plant Growth Regulators; Protein Kinase C; Tumor Cells, Cultured