The effect of cellular environment and p53 status on the mode of action of the platinum derivative LA-12.
In this study, we characterized the effects of LA-12 on tumor cell lines possessing wild type p53 and on p53-deficient/mutant cell lines and the results were compared to those obtained using cisplatin. We have determined changes of p53 levels, of its transcriptional activity, of its posttranscriptional modifications and the effect of the treatment on the cell cycle, on the induction of apoptosis and on gene expression. LA-12 induces weak accumulation of both transcriptionally active p53 tumor suppressor and of p21(WAF1/CIP1) protein. LA-12 and cisplatin also significantly differ in their effects on apoptosis and cell cycle and on gene expression spectra in studied cell lines. LA-12 induces higher apoptosis levels in comparison with those induced by cisplatin, especially in p53-deficient H1299 cells and in MCF-7DD cells with transcriptionally inactive p53. We suggest that LA-12-mediated apoptosis is not fully dependent on p53. This confirms the therapeutic potential of LA-12 as a more potent cytostatic agent for both tumor cells expressing wild type p53 and for p53-deficient or mutant cells.
Roubalová
Eva
E
Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Zlutý kopec 7, 656 53, Brno, Czech Republic.
Kvardová
Veronika
V
Hrstka
Roman
R
Borilová
Sárka
S
Michalová
Eva
E
Dubská
Lenka
L
Müller
Petr
P
Sova
Petr
P
Vojtesek
Borivoj
B
D000547:Amantadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; C482801:bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV); D000547:Amantadine; D002945:Cisplatin