Massaro R R, Faião-Flores F, Rebecca V W, Sandri S, Alves-Fernandes D K, Pennacchi P C, Smalley K S M, Maria-Engler S S
Department of Clinical Chemistry & Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
The Department of Tumor Biology, The Moffitt Cancer Center & Research Institute, Tampa, USA.
Pharmacol Res. 2017 May;119:242-250. doi: 10.1016/j.phrs.2017.02.013. Epub 2017 Feb 14.
Despite the recent advances in the clinical management of melanoma, there remains a need for new pharmacological approaches to treat this cancer. 2-methoxyestradiol (2ME) is a metabolite of estrogen that has shown anti-tumor effects in many cancer types. In this study we show that 2ME treatment leads to growth inhibition in melanoma cells, an effect associated with entry into senescence, decreased pRb and Cyclin B1 expression, increased p21/Cip1 expression and G2/M cell cycle arrest. 2ME treatment also inhibits melanoma cell growth in colony formation assay, including cell lines with acquired resistance to BRAF and BRAF+MEK inhibitors. We further show that 2ME is effective against melanoma with different BRAF and NRAS mutational status. Moreover, 2ME induced the retraction of cytoplasmic projections in a 3D spheroid model and significantly decreased cell proliferation in a 3D skin reconstruct model. Together our studies bring new insights into the mechanism of action of 2ME allowing melanoma targeted therapy to be further refined. Continued progress in this area is expected to lead to improved anti-cancer treatments and the development of new and more effective clinical analogues.
尽管黑色素瘤的临床管理最近取得了进展，但仍需要新的药理学方法来治疗这种癌症。2-甲氧基雌二醇（2ME）是雌激素的一种代谢产物，已在多种癌症类型中显示出抗肿瘤作用。在本研究中，我们表明2ME处理导致黑色素瘤细胞生长抑制，这种效应与进入衰老、pRb和细胞周期蛋白B1表达降低、p21/Cip1表达增加以及G2/M细胞周期阻滞有关。2ME处理在集落形成试验中也抑制黑色素瘤细胞生长，包括对BRAF和BRAF+MEK抑制剂获得性耐药的细胞系。我们进一步表明，2ME对具有不同BRAF和NRAS突变状态的黑色素瘤有效。此外，2ME在三维球体模型中诱导细胞质突起回缩，并在三维皮肤重建模型中显著降低细胞增殖。我们的研究共同为2ME的作用机制带来了新的见解，使黑色素瘤靶向治疗得以进一步完善。预计该领域的持续进展将带来改进的抗癌治疗方法，并开发出新的、更有效的临床类似物。
