2-2-bis(hydroxymethyl)-1-azabicyclo(2-2-2-)octan-3-one and Carcinoma--Non-Small-Cell-Lung

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.

Topics: Apoptosis Regulatory Proteins; Aza Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; DNA Fragmentation; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Lung Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53; Ultraviolet Rays

Mutant p53-carrying tumors are often more resistant to chemotherapeutical drugs. We demonstrate here that the mutant p53-reactivating compound PRIMA-1(MET) acts synergistically with several chemotherapeutic drugs to inhibit tumor cell growth. Combined treatment with cisplatin and PRIMA-1(MET) resulted in a synergistic induction of tumor cell apoptosis and inhibition of human tumor xenograft growth in vivo in SCID mice. The induction of mutant p53 levels by chemotherapeutic drugs is likely to increase the sensitivity of tumor cells to PRIMA-1(MET). Thus, the combination of PRIMA-1(MET) with currently used chemotherapeutic drugs may represent a novel and more efficient therapeutic strategy for treatment of mutant p53-carrying tumors.

Topics: Adenocarcinoma; Animals; Apoptosis; Aza Compounds; Bone Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Interactions; Drug Resistance, Neoplasm; Genes, p53; Humans; Lung Neoplasms; Mice; Mice, SCID; Mutation; Osteosarcoma; Quinuclidines; Transplantation, Heterologous; Tumor Cells, Cultured