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- Title
Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed.
- Authors
Li, Q; Kawamura, K; Yamanaka, M; Okamoto, S; Yang, S; Yamauchi, S; Fukamachi, T; Kobayashi, H; Tada, Y; Takiguchi, Y; Tatsumi, K; Shimada, H; Hiroshima, K; Tagawa, M
- Abstract
The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14ARF and the p16INK4A genes. We examined whether forced expression of p53 inhibited growth of mesothelioma cells and produced anti-tumor effects by a combination of cisplatin (CDDP) or pemetrexed (PEM), the first-line drugs for mesothelioma treatments. Transduction of mesothelioma cells with adenoviruses bearing the p53 gene (Ad-p53) induced phosphorylation of p53, upregulated Mdm2 and p21 expression levels and decreased phosphorylation of pRb. The transduction generated cleavage of caspase-8 and -3, but not caspase-9. Cell cycle analysis showed increased G0/G1- or G2/M-phase populations and subsequently sub-G1 fractions, depending on cell types and Ad-p53 doses. Transduction with Ad-p53 suppressed viability of mesothelioma cells and augmented the growth inhibition by CDDP or PEM mostly in a synergistic manner. Intrapleural injection of Ad-p53 and systemic administration of CDDP produced anti-tumor effects in an orthotopic animal model. These data collectively suggest that Ad-p53 is a possible agent for mesothelioma in combination with the first-line chemotherapeutics.
- Subjects
P53 antioncogene; GENE expression; APOPTOSIS; CELL-mediated cytotoxicity; CISPLATIN; MESOTHELIOMA; THERAPEUTICS
- Publication
Cancer Gene Therapy, 2012, Vol 19, Issue 3, p218
- ISSN
0929-1903
- Publication type
Article
- DOI
10.1038/cgt.2011.86