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

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).

• Authors: Elsa Charignon, Mathilde Bouché, Caroline Clave-Darcissac, Georges Dahm, Gabriel Ichim, Anthony Clotagatide, Hichem C Mertani, Philippe Telouk, Julie Caramel, Jean-Jacques Diaz, Stéphane Bellemin-Laponnaz, Philippe Bouvet, Claire Billotey
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 21 (Oct 22 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33105692 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BCL2L1 protein, human
• Heterocyclic Compounds
• Organoplatinum Compounds
• bcl-X Protein
• carbene
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Methane

Topics

• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Cell Death (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• DNA Breaks, Double-Stranded (drug effects)
• DNA Damage
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Screening Assays, Antitumor
• Heterocyclic Compounds (chemistry, pharmacology)
• Humans
• Melanoma (drug therapy, pathology)
• Methane (analogs & derivatives, chemistry)
• Organoplatinum Compounds (chemistry, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Skin Neoplasms (drug therapy, pathology)
• bcl-X Protein (metabolism)