PRIMA-1 synergizes with adriamycin to induce cell death in non-small cell lung cancer cells

R Magrini; D Russo; L Ottaggio; G Fronza; A Inga; P Menichini

doi:10.1002/jcb.21794

PRIMA-1 synergizes with adriamycin to induce cell death in non-small cell lung cancer cells

J Cell Biochem. 2008 Aug 15;104(6):2363-73. doi: 10.1002/jcb.21794.

Authors

R Magrini¹, D Russo, L Ottaggio, G Fronza, A Inga, P Menichini

Affiliation

¹ Molecular Mutagenesis and DNA Repair Unit, Department of Epidemiology and Prevention, National Cancer Research Institute (IST), Genova, Italy.

PMID: 18442053
DOI: 10.1002/jcb.21794

Abstract

p53-dependent apoptosis is important for the efficacy of cancer treatment, and tumors carrying mutant p53 are often resistant to chemotherapy. Non-small cell lung cancer (NSCLC) cells generally exhibit resistance to apoptosis following treatment with many cytotoxic drugs. The new molecule PRIMA-1 appears to kill human tumor cells by restoring the transcriptional activity to mutated p53. We investigated the induction of apoptosis in response to this drug in three NSCLC cell lines carrying different p53 proteins: A549 (p53wt), LX1 (p53R273H), and SKMes1 (p53R280K). PRIMA-1 alone did not trigger apoptosis but significantly reduced cell viability. However, in combination with adriamycin, PRIMA-1 strengthen the adriamycin-induced apoptosis in A549 and LX1. Interestingly, even in SKMes1 cells, the combined treatment triggered a strong PARP cleavage without DNA fragmentation. Our data suggest that in NSCLC cells, PRIMA-1 may induce cell death through pathways other than apoptosis but may synergize with adriamycin to trigger an apoptotic response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis Regulatory Proteins / metabolism
Aza Compounds / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Carcinoma, Non-Small-Cell Lung / pathology*
Cell Death / drug effects
Cell Death / radiation effects
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / radiation effects
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA Fragmentation / drug effects
DNA Fragmentation / radiation effects
Doxorubicin / pharmacology*
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Lung Neoplasms / pathology*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-mdm2 / metabolism
Tumor Suppressor Protein p53 / metabolism
Ultraviolet Rays

Substances

Apoptosis Regulatory Proteins
Aza Compounds
BBC3 protein, human
Bridged Bicyclo Compounds, Heterocyclic
Cyclin-Dependent Kinase Inhibitor p21
Proto-Oncogene Proteins
Tumor Suppressor Protein p53
Doxorubicin
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one