Apoptosis by \[Pt(O,O'-acac)(γ-acac)(DMS)\] requires PKC-δ mediated p53 activation in malignant pleural mesothelioma

Our plain-English summary of Apoptosis by [Pt(O,O'-acac)(γ-acac)(DMS)] requires PKC-δ mediated p53 activation in malignant pleural mesothelioma, by A. Muscella, C. Vetrugno, L.G. Cossa, et al (PloS One, 2017).

The study

• Authors: A. Muscella, C. Vetrugno, L.G. Cossa, G. Antonaci, A. Barca, S.A. De Pascali, F.P. Fanizzi, S. Marsigliante
• Journal: PloS One
• Published: 2017;12(7):e0181114
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma cancer cells have epithelioid or sarcomatoid morphology. The worst prognosis is associated with sarcomatoid phenotype and resistance to therapy is affected by cells heterogeneity. We recently showed that in ZL55 mesothelioma cell line of epithelioid origin [Pt(O,O'-acac)(γ-acac)(DMS)] (Ptac2S) has an antiproliferative effect in vitro and in vivo. Aim of this work was to extend the study on the effects of Ptac2S on ZL34 cell line, representative of sarcomatoid mesothelioma. ZL34 cells were used to assay the antitumor activity of Ptac2S in a mouse xenograft model in vivo. Then, both ZL34 and ZL55 cells were used in order to assess the involvement of p53 protein in (a) the processes underlying the sensitivity to chemotherapy and (b) the activation of various transduction proteins involved in apoptosis/survival processes. Ptac2S increases ZL34 cell death in vivo compared with cisplatin and, in vitro, Ptac2S was more efficacious than cisplatin in inducing apoptosis. In Ptac2S-treated ZL34 and ZL55 cells, p53 regulated gene products of apoptotic BAX and anti-apoptotic Bcl-2 proteins via transcriptional activation. Ptac2S activated PKC-δ and PKC-ε; their inhibition by PKC-siRNA decreased the apoptotic death of cells. PKC-δ was responsible for JNK1/2 activation that has a role in p53 activation. In addition, PKC-ε activation provoked phosphorylation of p38MAPK, concurring to apoptosis. In ZL34 cells, Ptac2S also activated PKC-α thus provoking ERK1/2 activation; inhibition of PKC-α, or ERK1/2, increased Ptac2S cytotoxicity. Results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, giving a substantial starting point for its further validation.

In plain English

This was a laboratory and animal study of Ptac2S, an experimental platinum drug, compared with the standard drug cisplatin in human malignant pleural mesothelioma cells. It did not study asbestos exposure. The authors used two cell lines: ZL34, representing the sarcomatoid type, and ZL55, representing the epithelioid type. ZL34 cells were implanted under the skin of nude mice. The mice then received one intravenous dose of saline, Ptac2S (10 mg/kg) or cisplatin (10 mg/kg). Over 5 weeks, mean tumour volume rose from 46.6 to 285.11 cubic millimetres in the saline group, to 251.87 in the cisplatin group (not significantly different from saline) and to 133.72 in the Ptac2S group. The Ptac2S group's tumours were significantly smaller than those of both other groups. No health problems were observed in the mice. In ZL34 cells grown in dishes, the concentration that halved cell survival, measured after 48 hours of treatment, was 4.64 micromolar for Ptac2S and 48.63 for cisplatin. In both cell lines, Ptac2S raised p53 and BAX and lowered Bcl-2. Blocking PKC-delta increased survival of Ptac2S-treated ZL34 cells. The authors concluded that Ptac2S is effective in pleural mesothelioma.

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 (cell culture) and animal experiment: human mesothelioma cell lines studied in vitro, plus a mouse xenograft model
• Who was studied: Human malignant pleural mesothelioma cell lines ZL34 (sarcomatoid) and ZL55 (epithelioid). The animal experiment used female athymic nude mice carrying ZL34 tumours; the figure legend gives 8 animals per group. The study was done at the University of Salento, Lecce, Italy.
• Exposure: Treatment with the platinum compound Ptac2S versus cisplatin; in mice, a single intravenous dose of 10 mg/kg of either drug or saline control. No asbestos or fiber exposure was studied.
• Main results:
  • In mice with ZL34 tumours, mean tumour volume rose over 5 weeks from 46.6 (plus or minus 6.78) to 285.11 (plus or minus 38.69) cubic mm in the saline group, to 251.87 (plus or minus 49.36) in the cisplatin group (p greater than 0.05) and to 133.72 (plus or minus 41.22) in the Ptac2S group.
  • Tumours in Ptac2S-treated mice were significantly smaller at each time point than in both control and cisplatin-treated mice (p less than 0.05).
  • No health problems were observed in the treated mice during the observation period.
  • In sarcomatoid ZL34 cells, the IC50 was 4.64 (plus or minus 0.13) micromolar for Ptac2S and 48.63 (plus or minus 0.72) micromolar for cisplatin (n = 6; p less than 0.001).
  • These IC50 values for ZL34 cells were calculated after 48 hours of treatment.
  • In both ZL34 and ZL55 cells, Ptac2S increased p53 and BAX protein levels and decreased Bcl-2.
  • Blocking PKC-delta with siRNA reduced Ptac2S-induced JNK1/2 activation, p53 and BAX induction, and Bcl-2 down-regulation. It also increased survival of Ptac2S-treated ZL34 cells.
  • Blocking PKC-epsilon with siRNA reduced p38MAPK activation.
  • In ZL34 cells, blocking PKC-alpha reduced ERK1/2 activation, and inhibiting ERK1/2 activation increased the cell-killing effect of Ptac2S.
• The authors' conclusion: The authors concluded that Ptac2S is effective in pleural mesothelioma and that the findings add to knowledge of the compound's anti-tumour activity.

Topics

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

Medical terms in this study, explained in our Lexicon: Apoptosis, Pleural Mesothelioma, Mesothelioma, Epithelioid, Sarcomatoid, Prognosis, Chemotherapy, Cisplatin.

Related studies

• In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma — A. Muscella, C. Vetrugno, et al. (2016)
• Editorial Note: Apoptosis by [Pt(O,O'-acac)(γ-acac)(DMS)] requires PKC-δ mediated p53 activation in malignant pleural mesothelioma — PLOS One Editors (2026)
• Inhibition of ZL55 cell proliferation by ADP via PKC-dependent signalling pathway — A. Muscella, L.G. Cossa, et al. (2018)
• 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)
• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, et al. (2015)
• Connexin 43 enhances Bax activation via JNK activation in sunitinib-induced apoptosis in mesothelioma cells — M. Uzu, H. Sato, et al. (2017)

Browse more research in PloS One, or return to medical research.