In Vitro and In Vivo Antitumor Activity of \[Pt(O,O'-acac)(γ-acac)(DMS)\] in Malignant Pleural Mesothelioma

Our plain-English summary of In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma, by A. Muscella, C. Vetrugno, L.G. Cossa, et al (PloS One, 2016).

The study

• Authors: A. Muscella, C. Vetrugno, L.G. Cossa, G. Antonaci, F. De Nuccio, S.A. De Pascali, F.P. Fanizzi, S. Marsigliante
• Journal: PloS One
• Published: 2016;11(11):e0165154
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy. There is an urgent need for effective therapy inasmuch as resistance, intrinsic and acquired, to conventional therapies is common. Among Pt(II) antitumor drugs, [Pt(O,O'-acac)(γ-acac)(DMS)] (Ptac2S) has recently attracted considerable attention due to its strong in vitro and in vivo antiproliferative activity and reduced toxicity. The purpose of this study was to examine the efficacy of Ptac2S treatment in MPM. We employed the ZL55 human mesothelioma cell line in vitro and in a murine xenograft model in vivo, to test the antitumor activity of Ptac2S. Cytotoxicity assays and Western blottings of different apoptosis and survival proteins were thus performed. Ptac2S increases MPM cell death in vitro and in vivo compared with cisplatin. Ptac2S was more efficacious than cisplatin also in inducing apoptosis characterized by: (a) mitochondria depolarization, (b) increase of bax expression and its cytosol-to-mitochondria translocation and decrease of Bcl-2 expression, (c) activation of caspase-7 and -9. Ptac2S activated full-length PKC-δ and generated a PKC-δ fragment. Full-length PKC-δ translocated to the nucleus and membrane, whilst PKC-δ fragment concentrated to mitochondria. Ptac2S was also responsible for the PKC-ε activation that provoked phosphorylation of p38. Both PKC-δ and PKC-ε inhibition (by PKC-siRNA) reduced the apoptotic death of ZL55 cells. Altogether, our results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, providing a solid starting point for its validation as a suitable candidate for further pharmacological testing.

In plain English

This laboratory study tested an experimental platinum compound, [Pt(O,O'-acac)(γ-acac)(DMS)] (called Ptac2S), against cisplatin, a standard chemotherapy drug, in malignant pleural mesothelioma. It did not study asbestos exposure. The authors used ZL55, a human mesothelioma cell line that the article says came from a patient with a known history of asbestos exposure. They grew the cells in dishes and as tumours under the skin of nude mice. In dishes, the concentration needed to reduce cell survival by half at 24 hours was 3.9 micromolar for Ptac2S and 46.8 micromolar for cisplatin, about 12-fold lower for Ptac2S. Ptac2S also triggered programmed cell death (apoptosis) faster. In mice (8 per group), average tumour volume reached 498.42 cubic millimetres with saline, 431.45 with cisplatin (not significantly different from saline) and 188.72 with Ptac2S. Mice given Ptac2S showed no significant weight loss. In ZL55 cells, blocking the cell proteins PKC-δ or PKC-ε reduced the cell death caused by Ptac2S. The authors concluded that Ptac2S might prove more effective than cisplatin for mesothelioma. The article describes the mouse experiment inconsistently between its methods and results sections.

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 a human mesothelioma cell line in culture plus an animal (mouse xenograft) experiment, comparing Ptac2S with cisplatin
• Who was studied: ZL55 human malignant pleural mesothelioma cells, which the article says were derived from a pleural epithelial tumour biopsy of a 52-year-old man with a known history of asbestos exposure. For the animal work, nude mice had ZL55 cells injected under the skin of the flank (8 animals per group).
• Exposure: Not an asbestos exposure study. The exposures were the experimental platinum drug Ptac2S and cisplatin (CDDP). In cell experiments the main comparisons used 5 micromolar Ptac2S and 50 micromolar cisplatin. In mice, a single intravenous injection was given of saline (control), Ptac2S, or 10 mg/kg cisplatin. The methods list Ptac2S doses of 5 and 10 mg/kg; the results report only 10 mg/kg.
• Main results:
  • In ZL55 cells, the concentration that halved survival at 24 hours (IC50) was 3.9 ± 0.11 micromolar for Ptac2S and 46.8 ± 0.6 micromolar for cisplatin (n = 6), about 12-fold greater cytotoxicity for Ptac2S
  • At 100 micromolar, Ptac2S killed about 50% of ZL55 cells after 7 hours; cisplatin at the same concentration took 18 hours to do so
  • 50% of ZL55 cells showed signs of apoptosis after 6 hours with Ptac2S, compared with 12 hours with cisplatin
  • Cisplatin activated caspase-3, but Ptac2S-treated cells showed no caspase-3 activation up to 24 hours
  • In mice, average tumour volume rose from 52.5 ± 17.22 to 498.42 ± 43.97 cubic millimetres in the saline group and to 431.45 ± 50.57 in the cisplatin group (p greater than 0.05)
  • In the Ptac2S-treated mice, average tumour volume reached 188.72 ± 32.53 cubic millimetres, significantly smaller at every time point than in untreated and cisplatin-treated mice (p less than 0.05)
  • The authors reported up to a 62% reduction in tumour mass with Ptac2S, compared with an average 10% inhibition with cisplatin
  • Mice receiving 10 mg/kg Ptac2S showed no significant loss of body weight
  • In ZL55 cells, blocking PKC-δ or PKC-ε with small interfering RNA reduced the apoptotic death caused by Ptac2S
  • Silencing PKC-ε blocked Ptac2S-induced p38MAPK activation and improved survival of Ptac2S-treated ZL55 cells
• The authors' conclusion: The authors concluded that ZL55 cells were much more sensitive to Ptac2S than to cisplatin, that Ptac2S greatly reduced tumour xenografts in mice, and that their findings suggest Ptac2S might prove more effective than cisplatin in treating malignant pleural mesothelioma
• Limitations the authors state:
  • The authors state that further studies are needed to identify the specific targets inside the cell of the protein p38

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: Pleural Mesothelioma, Chemotherapy, Mesothelioma, Apoptosis, Cisplatin, Translocation.

Related studies

• Apoptosis by [Pt(O,O'-acac)(γ-acac)(DMS)] requires PKC-δ mediated p53 activation in malignant pleural mesothelioma — A. Muscella, C. Vetrugno, et al. (2017)
• Antitumor activity of MEK and PI3K inhibitors against malignant pleural mesothelioma cells in vitro and in vivo — S. Miyoshi, H. Hamada, et al. (2012)
• Editorial Note: In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma — PLOS One Editors (2026)
• Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis — Y. Wang, A.K. Rishi, et al. (2011)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• ADP sensitizes ZL55 cells to the activity of cisplatin — A. Muscella, L.G. Cossa, et al. (2019)

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