ucn-1028-c and Leukemia--Myeloid

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

Calphostin C is a potent and specific inhibitor of protein kinase C (PKC). In this investigation we examined the effect of Calphostin C (without prior exposure to light) on daunorubicin (DNR) accumulation and sensitivity to DNR in multidrug-resistant (MDR) murine leukemia P388/ADR and human myeloid leukemia HL60/AR cells. P388/ADR cells overexpress P-glycoprotein, whereas HL60/AR cells lack any expression of P-glycoprotein (both at mRNA and protein levels). Calphostin C, in a concentration-dependent manner, increased the accumulation of DNR in P388/ADR cells and partially reversed (threefold) the DNR resistance in P388/ADR cells but had no effect on either of the parameters in HL60/AR cells. Calphostin C-induced increased accumulation of DNR in P388/ADR cells was due to increased uptake and decreased efflux of DNR. Furthermore, Calphostin C increased the uptake and decreased the efflux of rhodamine 123 (a substrate for P-gp) in P388/ADR cells but had no such effect in P388 cells. In addition, Calphostin C without exposure to light did not inhibit PKC activity in any of the cell lines studied. Taken together, these data suggest that Calphostin C may reverse drug resistance via P-glycoprotein independently of its effect on PKC activity. Therefore, any data regarding the effect of Calphostin C on the reversal of MDR should be interpreted in the light of these findings.

Topics: Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carrier Proteins; Coloring Agents; Daunorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Leukemia P388; Leukemia, Experimental; Leukemia, Myeloid; Membrane Glycoproteins; Mice; Naphthalenes; Polycyclic Compounds; Protein Kinase C; Rhodamine 123; Rhodamines; Tumor Cells, Cultured