Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed.
The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14(ARF) and the p16(INK4A) 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.
Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
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Q
Li
K
K
Kawamura
M
M
Yamanaka
S
S
Okamoto
S
S
Yang
S
S
Yamauchi
T
T
Fukamachi
H
H
Kobayashi
Y
Y
Tada
Y
Y
Takiguchi
K
K
Tatsumi
H
H
Shimada
K
K
Hiroshima
M
M
Tagawa
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000008:administration & dosage; D004789:Enzyme Activation; D005260:Female; D016158:Genes, p53; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000068437:Pemetrexed; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D005971:Glutamates; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000068437:Pemetrexed; D006147:Guanine; D020169:Caspases; D002945:Cisplatin