Abstract
The effects of PRIMA-1 on wild-type (WT) mouse leukemia L1210 cells and drug-resistant L1210 cells (Y8) were studied with respect to the induction of apoptosis and necrosis in these cell lines. The WT L1210 cells express mutant p53 while the Y8 L1210 cells do not express p53 mRNA or protein, but do express WAF1/p21 and Gadd 45 mRNA's and proteins. It was found that, in response to treatment with PRIMA-1, the WT L1210 cells became necrotic with little apoptosis while the Y8 L1210 cells showed a much higher level of apoptosis than necrosis. Flavopiridol in combination with PRIMA-1 caused a synergistic increase in necrosis in the WT L1210 cells while LY 294002 in combination with PRIMA-1 caused a synergistic increase in apoptosis in the Y8 L1210 cells. These studies showed that PRIMA-1 had an effect not only on cells expressing mutant p53, but also on cells that do not express p53, suggesting that PRIMA-1 and PRIMA-1-like molecules have multiple sites of action independent of restoring p53 function and that these can interact with other signaling pathways involving CDK's and PI3 kinases.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects
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Aza Compounds / administration & dosage
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Aza Compounds / pharmacology*
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Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Cycle / drug effects
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Chromones / administration & dosage
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Chromones / pharmacology
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Drug Resistance, Neoplasm
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Drug Synergism
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Flavonoids / administration & dosage
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Flavonoids / pharmacology
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Leukemia L1210 / drug therapy*
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Leukemia L1210 / genetics
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Leukemia L1210 / metabolism
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Leukemia L1210 / pathology*
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Mice
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Morpholines / administration & dosage
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Morpholines / pharmacology
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Necrosis
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Piperidines / administration & dosage
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Piperidines / pharmacology
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Tumor Suppressor Protein p53 / biosynthesis*
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
Substances
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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Cdkn1a protein, mouse
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Chromones
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Cyclin-Dependent Kinase Inhibitor p21
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Flavonoids
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Morpholines
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Piperidines
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Tumor Suppressor Protein p53
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Cyclin-Dependent Kinase Inhibitor p27
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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alvocidib
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one