Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma.
Because betulinic acid was recently described as a melanoma-specific inducer of apoptosis, we investigated whether this agent was comparably effective against metastatic tumors and those in which metastatic ability and 92-kD gelatinase activity had been decreased by introduction of a normal chromosome 6. Human metastatic C8161 melanoma cells showed greater DNA fragmentation and growth arrest and earlier loss of viability in response to betulinic acid than their non-metastatic C8161/neo 6.3 counterpart. These effects involved induction of p53 without activation of p21WAF1 and were synergized by bromodeoxyuridine in metastatic Mel Juso, with no comparable responses in non-metastatic Mel Juso/neo 6 cells. Our data suggest that betulinic acid exerts its inhibitory effect partly by increasing p53 without a comparable effect on p21WAF1.
Rieber
M
M
IVIC, Tumor Cell Biology Laboratory, Caracas, Venezuela. mrieber@pasteur.ivic.ve
Strasberg Rieber
M
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D018093:Gelatinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D000094062:Betulinic Acid
D000972:Antineoplastic Agents, Phytogenic; C534696:CCND3 protein, human; C493956:CDKN1A protein, human; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D018093:Gelatinases; D000094062:Betulinic Acid