In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma.
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.
Laboratory of Cell Pathology, Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
Antonella
A
Muscella
Laboratory of Cell Pathology, Department of Biological and Environmental Sciences and Technologies (Di.S.Te.B.A.), University of Salento, Lecce, Italy.
Carla
C
Vetrugno
Laboratory of Cell Physiology Di.S.Te.B.A., University of Salento, Lecce, Italy.
Luca Giulio
LG
Cossa
Laboratory of Cell Physiology Di.S.Te.B.A., University of Salento, Lecce, Italy.
Giovanna
G
Antonaci
Laboratory of Human Anatomy and Neuroscience, Di.S.Te.B.A., University of Salento, Lecce, Italy.
Francesco
F
De Nuccio
Laboratory of Inorganic Chemistry, Di.S.Te.B.A., University of Salento, Lecce, Italy.
Sandra Angelica
SA
De Pascali
Laboratory of Inorganic Chemistry, Di.S.Te.B.A., University of Salento, Lecce, Italy.
Francesco Paolo
FP
Fanizzi
Laboratory of Cell Physiology Di.S.Te.B.A., University of Salento, Lecce, Italy.
Santo
S
Marsigliante
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D051379:Mice; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C527556:Pt(O,O'-acac)(gamma-acac)(DMS); D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases