Instituto de Inmunología, Facultad de Medicina, Universidad Central de Venezuela, Apartado 50109, Caracas, 1050-A, Venezuela.
Instituto de Inmunología, Facultad de Medicina, Universidad Central de Venezuela, Apartado 50109, Caracas, 1050-A, Venezuela; Unidad de Biotecnología, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 50109, Caracas, 1050-A, Venezuela.
Eur J Pharmacol. 2019 Nov 5;862:172624. doi: 10.1016/j.ejphar.2019.172624. Epub 2019 Aug 23.
Caracasine acid (CA) is an ent-3,4-seco-kaurene isolated from the plant Croton micans. Decreased cancer cell lines viability was reported upon CA treatment. The present study aimed to investigate the mechanism of CA induced cytotoxicity using two human cell lines, Jurkat E6.1 (human cell T lymphoma) and HL-60 (human acute promyelocytic leukemia). Significant increases of apoptotic cell death markers upon CA treatment were observed: annexin-V positiveness, potential mitochondrial disturbances, cell cycle changes, caspase activation, and CD95 expression. These effects were not detected in normal lymphocytes. CA induced the appearance of Bax, cleaved caspase 3, and cytochrome c release in Jurkat cells, and cleaved caspase 3 and phosphorylated p53 in HL60 cells. Likewise, downregulation of anti-apoptotic proteins such as Bcl-x (Jurkat), Bcl-2, and XIAP (HL60) was observed with CA treatment. Both pathways, intrinsic and extrinsic were activated when cell lines were treated with CA. NF-κB p65 inhibition was observed in Jurkat cells and cell differentiation in HL-60 cells. CA could be a potential leader compound for the development of new drugs for leukemia treatment in humans.
卡瓦酸（CA）是从植物 Croton micans 中分离得到的一种 ent-3,4-seco-kaurene。CA 处理后，癌细胞系的活力降低。本研究旨在使用两种人类细胞系，Jurkat E6.1（人类 T 淋巴瘤细胞）和 HL-60（人类急性早幼粒细胞白血病），研究 CA 诱导细胞毒性的机制。CA 处理后观察到凋亡细胞死亡标志物显著增加：膜联蛋白-V 阳性、潜在的线粒体紊乱、细胞周期变化、半胱天冬酶激活和 CD95 表达。这些效应在正常淋巴细胞中未检测到。CA 诱导 Jurkat 细胞中 Bax、切割的 caspase 3 和细胞色素 c 的释放，以及 HL60 细胞中切割的 caspase 3 和磷酸化 p53 的表达。同样，CA 处理后观察到抗凋亡蛋白如 Bcl-x（Jurkat）、Bcl-2 和 XIAP（HL60）的下调。当用 CA 处理细胞系时，内在和外在途径都被激活。Jurkat 细胞中观察到 NF-κB p65 抑制，HL-60 细胞中观察到细胞分化。CA 可能是开发用于人类白血病治疗的新药的潜在先导化合物。
