Antiproliferative effects of some novel synthetic solanidine analogs on HL-60 human leukemia cells in vitro.
There is increasing evidence of the direct antiproliferative effects of various steroidal structures, including cardenolides, steroidal alkaloids and sexual hormones. The aim of the present study was to characterize the antiproliferative effects of three synthetic solanidine analogs (1-3) on HL-60 human leukemia cells. The three compounds exerted similar cytostatic effects (IC(50) values: 1.27-2.94 μM after a 72-h exposure) and the most effective (2) was selected for further investigations. Incubation with compound 2 resulted in a marked chromatin condensation followed by a gradual increase in cell membrane permeability detected by Hoechst dye 33258-propidium iodide double staining. A flow cytometric analysis revealed a marked decrease in the G1 phase and substantial increases in the S and G2/M phases after 24-h incubation, while after 48 h the proportion of cells in the subG1 phase was increased significantly with a concomitant decrease in cells in the G1 and G2/M phases. Compound 2 at 6.0 μM significantly decreased the activity of ribonucleotide reductase and proved to be a potent antioxidant in the lipid peroxidation and DPPH assays (IC(50) values: 2.0 and 13.1 μM, respectively). The antiproliferative effect of the test compound on the non-cancerous human lung fibroblast cell line (MRC-5) was significantly weaker than that on the leukemia cells. These results lead to the conclusion that compound 2 induces a marked disturbance in the cell cycle, which is, at least partially, a consequence of the inhibition of DNA synthesis.
Department of Pharmacodynamics and Biopharmacy, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary.
Renáta
R
Minorics
Thomas
T
Szekeres
Georg
G
Krupitza
Philipp
P
Saiko
Benedikt
B
Giessrigl
János
J
Wölfling
Eva
E
Frank
István
I
Zupkó
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004144:Diosgenin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008968:Molecular Conformation; D012264:Ribonucleotide Reductases / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000975:Antioxidants; D012264:Ribonucleotide Reductases; D004144:Diosgenin; C013255:solanidine