title: The proteasome inhibitor bortezomib acts differently in combination with p53 gene transfer or cytotoxic chemotherapy on NSCLC cells.
abstract: In this report, the effects of a combined treatment with the proteasome inhibitor bortezomib and either a recombinant adeno-associated virus type 2 (rAAV-2)-mediated p53 gene transfer or chemotherapeutic agents, docetaxel and pemetrexed, were tested on p53 positive and p53negative non-small cell lung cancer (NSCLC) cell lines. The combination of bortezomib and rAAV-p53 led to a significant synergistic inhibition of cell growth between 62-82% depending on the p53 status of the cell line and drug concentration. Surviving cells of the combined treatment showed a significant reduced ability to form colonies. Enhanced cell toxicity was associated with a 5.3-14.4-fold increase of the apoptotic rate and intracellular p53 level up to 50.4% following vector-mediated p53 restoration and bortezomib treatment. In contrast, an antagonistic effect on tumor cell growth and colony formation was observed for the combination of bortezomib and docetaxel or pemetrexed as a reduction of cell growth between 31 and 48% was found in comparison to 50% using the single agents. Lower cytotoxic effects were associated with significantly reduced apoptosis and an increase of clonogenic growth. The observed antagonistic effects between bortezomib and docetaxel or pemetrexed might influence clinical trials using these compounds. Conversely, p53 restoration and bortezomib treatment led to enhanced, synergistic tumor cell toxicity.
authors.affiliation: Klinik für Haematologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universitaet Duesseldorf, Duesseldorf, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Neukirchen
authors.forename: A
authors.initials: A
authors.lastname: Meier
authors.forename: A
authors.initials: A
authors.lastname: Rohrbeck
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Pardillos
authors.forename: U
authors.initials: U
authors.lastname: Steidl
authors.forename: R
authors.initials: R
authors.lastname: Fenk
authors.forename: R
authors.initials: R
authors.lastname: Haas
authors.forename: R
authors.initials: R
authors.lastname: Kronenwett
authors.forename: U-P
authors.initials: UP
authors.lastname: Rohr
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D000077143:Docetaxel; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy; D005971:Glutamates / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000628:therapy*; D000068437:Pemetrexed; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D005971:Glutamates; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D043823:Taxoids; D000068437:Pemetrexed; D000077143:Docetaxel; D006147:Guanine; D000069286:Bortezomib