Skin Biology Group, Clinical Chemistry and Toxicology Department, School of Pharmaceutical Sciences, University of Sao Paulo, FCF/USP, Brazil.
Butantan Institute, Pathophysiology Laboratory, Sao Paulo, Brazil.
Anticancer Agents Med Chem. 2020;20(9):1038-1050. doi: 10.2174/1871520620666200218111422.
Melanoma is the most aggressive skin cancer, and BRAF (V600E) is the most frequent mutation that led to the development of BRAF inhibitors (BRAFi). However, patients treated with BRAFi usually present recidivism after 6-9 months. Curcumin is a turmeric substance, and it has been deeply investigated due to its anti-inflammatory and antitumoral effects. Still, the low bioavailability and biodisponibility encouraged the investigation of different analogs. DM-1 is a curcumin analog and has shown an antitumoral impact in previous studies.
Evaluated DM-1 stability and cytotoxic effects for BRAFi-sensitive and resistant melanomas, as well as the role in the metalloproteinases modulation.
DM-1 showed growth inhibitory potential for melanoma cells, demonstrated by reduction of colony formation, migration and endothelial tube formation, and cell cycle arrest. Subtoxic doses were able to downregulate important Metalloproteinases (MMPs) related to invasiveness, such as MMP-1, -2 and -9. Negative modulations of TIMP-2 and MMP-14 reduced MMP-2 and -9 activity; however, the reverse effect is seen when increased TIMP-2 and MMP-14 resulted in raised MMP-2.
These findings provide essential details into the functional role of DM-1 in melanomas, encouraging further studies in the development of combinatorial treatments for melanomas.
黑色素瘤是最具侵袭性的皮肤癌，而 BRAF（V600E）是导致 BRAF 抑制剂（BRAFi）发展的最常见突变。然而，接受 BRAFi 治疗的患者通常在 6-9 个月后会出现复发。姜黄素是姜黄中的一种物质，由于其抗炎和抗肿瘤作用，已被深入研究。然而，由于其低生物利用度和生物可利用度，鼓励研究不同的类似物。DM-1 是一种姜黄素类似物，在先前的研究中显示出抗肿瘤作用。
评估 DM-1 对 BRAFi 敏感和耐药黑色素瘤的稳定性和细胞毒性作用，以及对金属蛋白酶调节的作用。
DM-1 对黑色素瘤细胞表现出生长抑制潜力，表现为集落形成、迁移和内皮管形成减少以及细胞周期停滞。亚毒性剂量能够下调与侵袭性相关的重要金属蛋白酶（MMPs），如 MMP-1、-2 和 -9。TIMP-2 和 MMP-14 的负调控降低了 MMP-2 和 -9 的活性；然而，当 TIMP-2 和 MMP-14 增加时，MMP-2 也会增加。
这些发现为 DM-1 在黑色素瘤中的功能作用提供了重要细节，鼓励进一步研究黑色素瘤联合治疗的开发。
