Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels

Our plain-English summary of Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels, by S. Okamoto, Y. Jiang, K. Kawamura, et al (PloS One, 2013).

The study

• Authors: S. Okamoto, Y. Jiang, K. Kawamura, M. Shingyoji, T. Fukamachi, Y. Tada, Y. Takiguchi, K. Tatsumi, H. Shimada, K. Hiroshima, H. Kobayashi, M. Tagawa
• Journal: PloS One
• Published: 2013;8(3):e60297
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

In plain English

This was a laboratory study of a possible drug treatment. It did not study people or asbestos exposure. The authors, working in Japan, tested zoledronic acid (ZOL), a drug used to prevent bone loss, on two human mesothelioma cell lines, MSTO-211H and EHMES-10. Both cell lines carry the normal (wild-type) p53 gene. The authors also tested ZOL in mice with mesothelioma cells placed in the pleural cavity. ZOL killed both cell lines, more so at higher doses. Combined with the chemotherapy drug cisplatin, ZOL worked synergistically in MSTO-211H cells and additively, or possibly slightly synergistically, in EHMES-10 cells. In mice, the combination reduced tumor weights more than either drug alone. ZOL raised levels of the p53 protein. When the authors lowered p53, ZOL's own killing effect barely changed, but the extra effect of the combination disappeared. ZOL also added to the effect of a virus carrying the p53 gene. The authors concluded that ZOL injected into the pleural cavity together with cisplatin is a potential treatment for mesothelioma. They noted that ZOL seems less effective outside bone.

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: experiments on human mesothelioma cell lines plus an animal experiment in mice
• Who was studied: Two human mesothelioma cell lines, MSTO-211H and EHMES-10, both with wild-type p53. Also female BALB/c nu/nu (nude) mice, 6 weeks old, with MSTO-211H cells injected into the pleural cavity (the figure legend gives n = 6). The work was done in Japan.
• Exposure: No asbestos exposure was studied. The treatments tested were zoledronic acid (ZOL), alone and combined with cisplatin (CDDP) or with an adenovirus carrying the p53 gene (Ad-p53).
• Main results:
  • Both mesothelioma cell lines were killed by ZOL, more so at higher doses.
  • Combined with cisplatin, ZOL killed cells synergistically in MSTO-211H cells and additively, or possibly slightly synergistically, in EHMES-10 cells.
  • In the mouse model, ZOL plus cisplatin reduced tumor weights more than either drug alone. The authors noticed no body weight loss in the combination group.
  • ZOL raised p53 protein levels in both cell lines.
  • Lowering p53 with siRNA barely affected ZOL's own killing effect, which the authors took to suggest that effect was independent of p53.
  • Lowering p53 with siRNA cancelled the combined effect of ZOL and cisplatin in both cell lines.
  • ZOL combined with the p53-carrying virus (Ad-p53) produced additive, or possibly slightly synergistic, effects.
• The authors' conclusion: The authors concluded that ZOL combined with cisplatin or Ad-p53 produced better effects than either agent alone. They presumed that ZOL injected into the pleural cavity, combined with cisplatin, is a potential treatment for mesothelioma.
• Limitations the authors state:
  • ZOL's anti-tumor effects seem weaker outside bone, because the drug is quickly cleared by the kidney.
  • The authors speculated, but had not shown, that injection into the pleural cavity keeps ZOL concentrations high at the tumor.
  • How ZOL raises p53 remains unclear.
  • The control siRNA unexpectedly killed MSTO-211H cells, for reasons not known.

Topics

Medical terms in this study, explained in our Lexicon: Cisplatin, Mesothelioma, Pleural Cavity.

Related studies

• Zoledronic acid produces antitumor effects on mesothelioma through apoptosis and S-phase arrest in p53-independent and Ras prenylation-independent manners — S. Okamoto, K. Kawamura, et al. (2012)
• Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed — Q. Li, K. Kawamura, et al. (2012)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Effect of IL-18 on expansion of gammadelta T cells stimulated by zoledronate and IL-2 — W. Li, S. Kubo, et al. (2010)
• Pharmacological targeting of p53 through RITA is an effective antitumoral strategy for malignant pleural mesothelioma — D. Di Marzo, I.M. Forte, et al. (2014)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)

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