通过抑制FAK激活，抗骨化酸的酰胺衍生物在三阴性乳腺癌细胞中诱导非凋亡细胞死亡。
The amide derivative of anticopalic acid induces non-apoptotic cell death in triple-negative breast cancer cells by inhibiting FAK activation.
发表日期：2023 Aug 18
作者：
Pornsuda Chawengrum, Natthaorn Luepongpatthana, Sanit Thongnest, Jitnapa Sirirak, Jutatip Boonsombat, Kriengsak Lirdprapamongkol, Siriporn Keeratichamroen, Patcharin Kongwaen, Phreeranat Montatip, Prasat Kittakoop, Jisnuson Svasti, Somsak Ruchirawat
来源：
Cell Death & Disease
摘要：
从Kaempferia elegans的根茎中提取的一种龙脑类二萜类化合物——抗病菌酸（ACP）及其21个半合成衍生物被评估其抗癌细胞毒活性。在九种癌细胞系列中，大多数衍生物表现出比母化合物ACP更高的细胞毒活性。在测试的化合物中，酰胺4p对白血病细胞系列HL-60和MOLT-3显示出最高的细胞毒活性，其IC50值分别为6.81 ± 1.99和3.72 ± 0.26 µM。更有趣的是，酰胺衍生物4l对三阴性乳腺癌细胞系列MDA-MB-231表现出细胞毒活性，其IC50为13.73 ± 0.04 µM，而MDA-MB-231被认为是最具侵袭性的乳腺癌类型。机制研究表明，4l通过非凋亡调节性细胞死亡诱导MDA-MB-231细胞死亡。另外，西方印迹分析显示，化合物4l浓度依赖性地降低了FAK蛋白的磷酸化。分子对接模拟阐明，化合物4l可能通过与FAK激酶结构域中的一个磷酸酶结合口袋，来潜在地抑制FAK的激活。数据表明，化合物4l对于治疗三阴性乳腺癌可能是一个潜在的FAK抑制剂，并值得进一步研究。© 2023. Springer Nature Limited.
Anticopalic acid (ACP), a labdane type diterpenoid obtained from Kaempferia elegans rhizomes, together with 21 semi-synthetic derivatives, were evaluated for their cancer cytotoxic activity. Most derivatives displayed higher cytotoxic activity than the parent compound ACP in a panel of nine cancer cell lines. Among the tested compounds, the amide 4p showed the highest cytotoxic activity toward leukemia cell lines, HL-60 and MOLT-3, with IC50 values of 6.81 ± 1.99 and 3.72 ± 0.26 µM, respectively. More interestingly, the amide derivative 4l exhibited cytotoxic activity with an IC50 of 13.73 ± 0.04 µM against the MDA-MB-231 triple-negative breast cancer cell line, which is the most aggressive type of breast cancer. Mechanistic studies revealed that 4l induced cell death in MDA-MB-231 cells through non-apoptotic regulated cell death. In addition, western blot analysis showed that compound 4l decreased the phosphorylation of FAK protein in a concentration-dependent manner. Molecular docking simulations elucidated that compound 4l could potentially inhibit FAK activation by binding to a pocket of FAK kinase domain. The data suggested that compound 4l could be a potential FAK inhibitor for treating triple-negative breast cancer and worth being further investigated.© 2023. Springer Nature Limited.