Molecular mechanisms involved in the antiproliferative action of protein tyrosine phosphatase inhibitor potassium bisperoxo(1,10-phenanthroline)oxovanadate.
Potassium bisperoxo(1,10-phenanthroline)oxovanadate, bpV(phen), a powerful protein phosphotyrosine phosphatase inhibitor and a potent insulinomimetic, influenced three fundamental cellular processes in HL-60 human leukemic cells: 1) inhibition of proliferation, 2) induction of differentiation and 3) apoptotic cell death. In the presence of micromolar concentrations of bpV(phen) cell number and DNA synthesis decreased progressively with time of incubation. A single treatment with bpV(phen) (3 microM) activated a differentiation program; after 6 days of incubation 82% of cells were differentiated, but differentiation started already within the first 24 h. Concentrations of 5-10 microM bpV(phen) caused the characteristic DNA ladder pattern, starting after 4.5 h. Differentiation in HL-60 cells appear to be associated with activation of extracellular signal-regulated kinase while apoptosis is connected with phosphorylation and activation of both extracellular signal-regulated kinase and c-Jun N-terminal kinase in a concentration and time-dependent manner. The antiproliferative and apoptotic action of bpV(phen) could be exploited in combination chemotherapy in leukemia.
Ban
J
J
Department of Molecular Biology, Faculty of Science, University of Zagreb, Croatia. jban@rudjer.irb.hr
Maysinger
D
D
Kovac
V
V
Galetić
I
I
Matulić
M
M
Hadzija
M
M
Uzarević
B
B
D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010618:Phenanthrolines / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013997:Time Factors
D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D009942:Organometallic Compounds; D010618:Phenanthrolines; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D004247:DNA; D017027:Protein Tyrosine Phosphatases