Mechanisms of antitumor action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy)benzoate: drug-induced protein dephosphorylations and inhibition of the permissive action of ceramide on growth factor induced cell proliferation.
The tumoricidal mechanism of methyl-3,5-diiodo-4-(4'-methoxypropoxy)benzoate (DIME), or DIPE, has been analyzed beyond its first recognized cellular site, which is the inhibition of tubulin polymerization. DIME (or DIPE) pretreatment of Eras cells for 3 days abolished ceramide basic fibroblast growth factor (bFGF)-induced glycolysis, coinciding with a block produced by the phosphoprotein dephosphorylation of cdc 25 by protein phosphatase 2A (PP2A). Protein dephosphorylation is directly activated by DIME (or DIPE), and enzyme activities that are dependent on P-proteins are significantly down-regulated (e.g. Topo I and II, MAP-kinase, and cdc-cyclin kinase). Purified PP2A is one target of activation by DIME (or DIPE), and an alkaline phosphatase isoenzyme is also induced by the drug. It is proposed that the pleiotropic effects of DIME (or DIPE) on cancer cells involve the activation of protein dephosphorylations, as well as inhibition of tubulin polymerization.
Bauer
Pal I
PI
Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary.
Kirsten
Eva
E
Kun
Ernest
E
D000469:Alkaline Phosphatase / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002518:Ceramides / Q000494:pharmacology; D015536:Down-Regulation; D042783:Endothelial Cells; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007463:Iodobenzoates / Q000494:pharmacology*; D010766:Phosphorylation; D011108:Polymers; D011506:Proteins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D002518:Ceramides; D006133:Growth Substances; D007463:Iodobenzoates; D011108:Polymers; D011506:Proteins; D014404:Tubulin; C436733:methyl 3,5-diiodo-4-(4'-methoxyphenoxy)benzoate; D000469:Alkaline Phosphatase