Hospices Civils de Lyon, EA3738-Therapeutic Targeting in Oncology, Université Jean Monnet-Université Claude Bernard Lyon1, 165 Chemin du Grand Revoyet, CEDEX, 69921 Oullins, France.
INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Université Claude Bernard Lyon1, CEDEX 08, 69373 Lyon, France.
Int J Mol Sci. 2020 Oct 22;21(21):7826. doi: 10.3390/ijms21217826.
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).
我们在这里描述了两种带有氮杂环卡宾（NHC）配体、吡啶配体和溴化物或碘化物配体的铂（II）配合物对一组人转移性皮肤黑素瘤细胞系的细胞毒性功效的评估，这些细胞系代表了不同的遗传亚群，包括 BRAF 抑制剂耐药细胞系，即 A375、SK-MEL-28、MeWo、HMCB、A375-R、SK-MEL-5-R 和 501MEL-R。顺铂和达卡巴嗪也被研究用于比较目的。值得注意的是，碘标记的 Pt-NHC 配合物在 1 小时暴露后强烈抑制了所有测试的黑素瘤细胞的增殖，这可能是由于其被黑素瘤细胞快速摄取。这种抑制活性的机制涉及 DNA 双链断裂和细胞凋亡的形成。考虑到当前系统治疗转移性黑素瘤细胞的固有化疗耐药性，这些发现很有希望，并为未来提供了研究机会，以改善目前无法切除的转移性黑素瘤患者的预后，这些患者不符合条件或对目前最有效的药物没有反应，即 BRAF 抑制剂和抗 PD-1 单克隆抗体（mAb）。
