INSERM, U1065, Equipe 12, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 route de saint Antoine de Ginestière, 06204, Nice cedex 3, France.
Equipe Labellisée Fondation pour la Recherche Médicale (FRM) 2020, Paris, France.
Cell Death Dis. 2021 Jan 11;12(1):64. doi: 10.1038/s41419-020-03344-6.
In the search of biguanide-derived molecules against melanoma, we have discovered and developed a series of bioactive products and identified the promising new compound CRO15. This molecule exerted anti-melanoma effects on cells lines and cells isolated from patients including the ones derived from tumors resistant to BRAF inhibitors. Moreover, CRO15 was able to decrease viability of cells lines from a broad range of cancer types. This compound acts by two distinct mechanisms. First by activating the AMPK pathway induced by a mitochondrial disorder. Second by inhibition of MELK kinase activity, which induces cell cycle arrest and activation of DNA damage repair pathways by p53 and REDD1 activation. All of these mechanisms activate autophagic and apoptotic processes resulting in melanoma cell death. The strong efficacy of CRO15 to reduce the growth of melanoma xenograft sensitive or resistant to BRAF inhibitors opens interesting perspective.
在寻找针对黑色素瘤的双胍衍生分子的过程中，我们发现并开发了一系列具有生物活性的产品，并确定了有前途的新化合物 CRO15。该分子对包括对 BRAF 抑制剂耐药的肿瘤衍生的细胞系和患者分离的细胞具有抗黑色素瘤作用。此外，CRO15 能够降低来自广泛类型癌症的细胞系的活力。该化合物通过两种不同的机制起作用。首先，通过激活由线粒体紊乱引起的 AMPK 途径。其次，通过抑制 MELK 激酶活性，该活性通过 p53 和 REDD1 激活诱导细胞周期停滞和 DNA 损伤修复途径的激活。所有这些机制都激活自噬和凋亡过程，导致黑色素瘤细胞死亡。CRO15 有效抑制对 BRAF 抑制剂敏感或耐药的黑色素瘤异种移植物的生长，为治疗黑色素瘤提供了新的思路。
