Department of Drug Sciences, University of Catania, Catania, Italy.
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Phytother Res. 2019 Dec;33(12):3242-3250. doi: 10.1002/ptr.6498. Epub 2019 Sep 5.
Isocordin 1 and a series of 4-oxyalkyl-isocordoin analogues 2-8 were evaluated for their cytotoxicity effect against human melanoma cells (A2058). Analogues 4, 5, and 6 showed a higher inhibitory activity with IC values of 12.91 ± 0.031, 24.88 ± 0.013, and 11.62 ± 0.017, respectively. These analogues, 4, 5, and 6, also induced an apoptotic response at 12.5- and 25-μM concentrations. They inhibited the expression of antiapoptotic proteins Bcl-2 and Hsp70, a critical factor that promotes tumour cell survival. In contrast, Bax and caspase-9 expression, and caspase-3 enzyme resulted activated. These results were correlated to a DNA fragmentation typical of apoptosis and an increase of intracellular reactive oxygen species (ROS) levels. Alternatively, at higher concentration (50 μM), when the capacity of the cells to sustain Hsp70 synthesis is reduced, our results seem to indicate that necrosis was induced by a further increase in ROS production. Therefore, the central finding in the present study is that these molecules downregulates Hsp70 expression. Altogether, these results suggest that 4-oxyalkyl-isocordoin analogues 4, 5, and 6 deserve to be deeply investigated for a possible application as Hsp70 inhibitor in the management of melanoma.
Isocordin 1 和一系列 4-氧代烷基异柯蒂因类似物 2-8 被评估了它们对人黑色素瘤细胞（A2058）的细胞毒性作用。类似物 4、5 和 6 表现出更高的抑制活性，IC 值分别为 12.91±0.031、24.88±0.013 和 11.62±0.017。这些类似物 4、5 和 6 在 12.5 和 25 μM 浓度下也诱导了凋亡反应。它们抑制了抗凋亡蛋白 Bcl-2 和 Hsp70 的表达，这是促进肿瘤细胞存活的关键因素。相比之下，Bax 和 caspase-9 的表达以及 caspase-3 酶被激活。这些结果与凋亡的典型 DNA 片段化和细胞内活性氧 (ROS) 水平的增加相关。另一方面，在较高浓度（50 μM）下，当细胞维持 Hsp70 合成的能力降低时，我们的结果似乎表明坏死是由 ROS 产生的进一步增加引起的。因此，本研究的主要发现是这些分子下调 Hsp70 的表达。总的来说，这些结果表明 4-氧代烷基异柯蒂因类似物 4、5 和 6 值得深入研究，以作为 HSP70 抑制剂应用于黑色素瘤的治疗。
