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

Antonella Muscella,Santo Marsigliante,Luca Giulio Cossa,Sandra Angelica De Pascali,Francesco Paolo Fanizzi,Amilcare Barca,Carla Vetrugno,Giovanna Antonaci,Yi-Hsien Hsieh

doi:10.1371/journal.pone.0181114

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.

Highlights

The incidence of malignant pleural mesothelioma (MPM) is growing due to wide asbestos usage in various developing countries [1]
When cancers reached the size of ~50 mm3, in order to reduce weight and tumour size odds, mice were randomized in three groups. 10 mg/kg of Ptac2S was found before to be effective without notable side effects in animal studies with xenografts of human breast cancerous cells [11]
In mice inoculated with ZL34, during 5 weeks mean tumour volume augmented from 46.6 ±6.78 to 285.11±38.69 mm3 for the saline group, to 251.87±49.36 mm3 for the cisplatin group (10mg/kg; p>0.05) and to 133.72±41.22 mm3 for the Ptac2S group (Fig 1)

Summary

Introduction

The incidence of malignant pleural mesothelioma (MPM) is growing due to wide asbestos usage in various developing countries [1]. Apoptosis by Ptac2S requires PKC-δ mediated p53 activation in malignant pleural mesothelioma bromide; PK, pharmacokinetics; Ptac2S, [Pt(O,O0acac)(γ-acac)(DMS)]; SRB, sulforhodamine B. and cisplatin; the median survival is 12 months, with response rates of about 40% [2, 3]. Biologic agents targeting oncogenetic pathways, such as histone deacetylases, phosphatidylinositol 3-kinase /mammalian target of rapamycin, nuclear factor kB and neoangiogenesis have been tested [4] None of these treatments showed to impact significantly on this neoplasm; there is an urgent need for new drugs. Pharmacokinetics studies with Ptac2S uncovered lengthened systemic blood persistence of Pt and diminished nephrotoxicity and hepatotoxicity In principle, this Pt-compound would yield a wider use, since Ptac2S exerts specific antimetastatic responses in vitro [13,14]. We looked for the differences between responses to Ptac2S and cisplatin and the molecular mechanisms that determine the ZL34 cell death/survival fate

Methods

Results

Conclusion