In Cellulo Evaluation of the Therapeutic Potential of NHC Platinum Compounds in Metastatic Cutaneous Melanoma.

Georges Dahm,Elsa Charignon,Philippe Bouvet,Jean-Jacques Diaz,Mathilde Bouché,Philippe Telouk,Stéphane Bellemin-Laponnaz,Claire Billotey,Gabriel Ichim,Anthony Clotagatide,Hichem C Mertani,Caroline Clave-Darcissac,Julie Caramel

doi:10.3390/ijms21217826

Abstract

We describe here the evaluation of the cytotoxic efficacy of two platinum (II) complexes bearing an N-heterocyclic carbene (NHC) ligand, a pyridine ligand and bromide or iodide ligands on a panel of human metastatic cutaneous melanoma cell lines representing different genetic subsets including BRAF-inhibitor-resistant cell lines, namely A375, SK-MEL-28, MeWo, HMCB, A375-R, SK-MEL-5-R and 501MEL-R. Cisplatin and dacarbazine were also studied for comparison purposes. Remarkably, the iodine-labelled Pt-NHC complex strongly inhibited proliferation of all tested melanoma cells after 1-h exposure, likely due to its rapid uptake by melanoma cells. The mechanism of this inhibitory activity involves the formation of DNA double-strand breaks and apoptosis. Considering the intrinsic chemoresistance of metastatic melanoma cells of current systemic treatments, these findings are promising and could give research opportunities in the future to improve the prognosis of patients suffering from unresectable metastatic melanoma that are not eligible or that do not respond to the most effective drugs available to date, namely BRAF inhibitors and the anti-PD-1 monoclonal antibody (mAb).

Highlights

The incidence of cutaneous melanoma and other skin cancers has dramatically increased over the past five decades in Caucasian populations that are exposed to intense and frequent ultraviolet radiation [1], resulting in an estimated 100-fold difference in the rate of melanoma incidence between Australia and India in 2012 [2]
We describe here the evaluation of the cytotoxic efficacy of two platinum (II) complexes bearing an N-heterocyclic carbene (NHC) ligand, a pyridine ligand and bromide or iodide ligands on a panel of human metastatic cutaneous melanoma cell lines representing different genetic subsets including BRAF-inhibitor-resistant cell lines, namely A375, SK-MEL-28, MeWo, HMCB, A375-R, SK-MEL-5-R and 501MEL-R
Based on our knowledge of the mode of action of cisplatin and of the pathways activated in tumor cells, we investigated the interaction of these NHC-Pt compounds with cells, as well as the cell death pathways triggered by such an exposure

Summary

Introduction

The incidence of cutaneous melanoma and other skin cancers has dramatically increased over the past five decades in Caucasian populations that are exposed to intense and frequent ultraviolet radiation [1], resulting in an estimated 100-fold difference in the rate of melanoma incidence between Australia and India in 2012 [2]. At the metastatic stage, cutaneous melanoma cells invade lymph nodes (known as stage IIIC for unresectable lymph node metastasis) and/or distant organs (stage IV), and require systemic procedures, except in the case of skin and/or lymph node metastases of limited sizes [7,8], with the aim of prolonging life and symptom-free survival beyond several months. Most metastatic cutaneous melanoma patients with mutated BRAF-V600 (around 40–50%) exhibit a spectacular and rapid initial response to the BRAF inhibitor treatments, which significantly enhances their overall survival (OS) and progression-free survival (PFS) compared to conventional chemotherapy, without resulting in a higher level of toxicity [2]. Many patients become secondarily resistant (i.e., their status reverts from “responder” to “non-responder”) upon treatment [3,6] and some develop important side effects among which is the onset of new primary BRAF wild type (BRAF-wt) cutaneous melanoma, likely due to the paradoxical activation of the MAPK pathway by BRAF inhibitors [5]

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