Comparative effects of protein phosphatase inhibitors (okadaic acid and calyculin A) on human leukemia HL60, HL60/ADR and K562 cells.
Inhibitors of protein phosphatases 1/2A (okadaic acid and calyculin A) exhibited differential cytotoxicity toward three human leukemia cell lines, in an increasing order of resistance, HL60 less than HL60/ADR less than K562 cells. Cytotoxicity of the toxins was associated with marked mitotic arrest of the cells, characterized by chromatid scattering/overcondensation and abnormal mitotic spindles. In all cases, calyculin A was more potent than okadaic acid. Protein phosphorylation experiments in intact cells revealed that HL60/ADR, the adriamycin-resistant variant, showed a higher overall phosphorylation of nuclear proteins than the drug-sensitive parental HL60, and that phorbol ester (protein kinase C activator) and calyculin A appeared to more specifically stimulate phosphorylation of p66 and p60, respectively. It was suggested that the toxins might be useful in delineating mechanisms underlying certain properties of cancer cells (such as multidrug resistance, mitosis and differentiation) related to protein phosphorylation/dephosphorylation reactions.
Sakurada
K
K
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322.
Zheng
B
B
Kuo
J F
JF
D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004988:Ethers, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008387:Marine Toxins; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D019319:Okadaic Acid; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D014407:Tumor Cells, Cultured
D004988:Ethers, Cyclic; D008387:Marine Toxins; D009687:Nuclear Proteins; D010080:Oxazoles; D019319:Okadaic Acid; C059041:calyculin A; D010749:Phosphoprotein Phosphatases