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

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.

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

“…As stated above, activated MAPKs are involved in apoptosis [43] also when apoptosis is due to Ptac2S, as shown in human neuroblastoma and breast cancer cells [8, 9]. We have show that Ptac2S causes activation of p38MAPK in ZL55 cells [12], and in the present paper we also show that Ptac2S causes activation of MAPKs and that p38MAPK and JNK1/2 have a pro-apoptotic role in both ZL34 and ZL55. The activation of PKC-ε in Ptac2S treated cells is accountable for the sustained p38MAPK phosphorylation.…”

Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0

“….. The maximum size the tumors allowed to grow in the mice before euthanasia was 2000 mm 3 ' [222]. signs of leukemia or other adverse events, and had no abnormal tissues when it was autopsied.…”

“…Health was monitored by weight (twice weekly), food and water intake, and general assessment of animal activity, panting, and fur condition…. The maximum size the tumors allowed to grow in the mice before euthanasia was 2000 mm 3 ’ [ 222 ].…”

Response of Cisplatin Resistant Skov-3 Cells to [Pt(O,O′-Acac)(γ-Acac)(DMS)] Treatment Revealed by a Metabolomic 1H-NMR Study

“…On the other hand, the alternative action mechanism of Ptac2S (essentially cytosolic) might be responsible for the ability of this potential anticancer agent to overcome the drug resistance induction, one of the principal causes of cisplatin-based tumor treatment failure [ 46 ]. Indeed, Ptac2S has shown a higher in vitro and in vivo pharmacological activity and tolerability than cisplatin [ 47 , 48 , 49 ], making it an attractive alternative to cisplatin for the treatment of different tumor.…”