Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

Our plain-English summary of Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed, by Q. Li, K. Kawamura, M. Yamanaka, et al (Cancer Gene Therapy, 2012).

The study

• Authors: Q. Li, K. Kawamura, M. Yamanaka, S. Okamoto, S. Yang, S. Yamauchi, T. Fukamachi, H. Kobayashi, Y. Tada, Y. Takiguchi, K. Tatsumi, H. Shimada, K. Hiroshima, M. Tagawa
• Journal: Cancer Gene Therapy
• Published: 2012;19(3):218-28
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This laboratory study tested a gene-therapy approach on mesothelioma cells, not asbestos exposure. The authors used a disabled adenovirus to carry the p53 gene into five human mesothelioma cell lines. A control virus carrying an unrelated gene (Ad-LacZ) served as comparison. The p53 virus, but not the control, lowered cell viability in a dose-dependent way in all lines except NCI-H2052; the authors reported that greater amounts of Ad-p53 overcame that insensitivity. It switched on the cell-death enzymes caspase-8 and caspase-3 but not caspase-9. Combined with cisplatin or pemetrexed, the effect was mostly synergistic (more than additive); the exceptions were NCI-H2452, with minimal synergism between 0.3 and 0.6 at fraction affected for cisplatin, and NCI-H28, with slight inhibitory effects at a lower fraction affected range for pemetrexed. In mice with mesothelioma cells placed in the chest cavity, the p53 virus reduced tumor weight in a dose-dependent way. Adding cisplatin reduced tumor weight more than either treatment alone. Pemetrexed was not tested in mice. The authors noted that two of their assays did not fully agree, and proposed the combination as a possible treatment strategy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human mesothelioma cell lines, plus an animal experiment in mice (orthotopic model, with tumor cells placed in the chest cavity)
• Who was studied: Five human mesothelioma cell lines (NCI-H2452, NCI-H2052, NCI-H226, NCI-H28 and MSTO-211H), all lacking the p14 and p16 genes but carrying normal (wild-type) p53. Also 6-week-old female BALB/c nude mice.
• Exposure: Not asbestos. The treatments tested were a replication-incompetent adenovirus carrying the wild-type p53 gene (Ad-p53), alone or with cisplatin (CDDP) or pemetrexed (PEM). A virus carrying the beta-galactosidase gene (Ad-LacZ) served as the control.
• Main results:
  • In the cell lines, Ad-p53 but not Ad-LacZ reduced viability in a dose-dependent way in all lines except NCI-H2052.
  • The authors reported that larger amounts of Ad-p53 did suppress growth of the insensitive NCI-H2052 cells, with the supporting data not shown.
  • In MSTO-211H and NCI-H28 cells, Ad-p53 caused cleavage (activation) of caspase-3 and caspase-8 but not caspase-9.
  • In the cell lines, combination index values showed Ad-p53 plus cisplatin was synergistic in most lines; NCI-H2452 showed only minimal synergism between 0.3 and 0.6 at fraction affected.
  • In the cell lines, Ad-p53 plus pemetrexed was synergistic except in NCI-H28 cells, which showed slight inhibitory effects at a lower fraction affected range.
  • NCI-H2052 cells, which resisted Ad-p53 alone, became more sensitive to cisplatin and to pemetrexed when given Ad-p53 than when given Ad-LacZ.
  • In mice, Ad-p53 injected into the chest cavity reduced tumor weight on day 28 in a dose-dependent way; Ad-LacZ did not change tumor weight.
  • In mice, Ad-p53 plus cisplatin reduced tumor weight more than either treatment alone.
• The authors' conclusion: The authors proposed that injecting Ad-p53 into the chest cavity, together with first-line chemotherapy given to the whole body, could be a treatment strategy for mesothelioma.
• Limitations the authors state:
  • The combination of Ad-p53 and pemetrexed was not tested in mice, because a suitable pemetrexed dose for mice was hard to determine.
  • The cell viability test and the cell cycle analysis did not fully agree on which cell lines were most susceptible to Ad-p53.
  • The authors stated that Ad-p53 needs to be compared with Ad-p14 or Ad-p16 to judge its effectiveness as a treatment.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Cisplatin, Pemetrexed (Alimta), Malignant Mesothelioma.

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