Monasterio Alberto, Urdaci María C, Pinchuk Irina V, López-Moratalla Natalia, Martínez-Irujo Juan J
Departamento di Bioquímica y Biología Molecular, Universidad de Navarra, Pamplona, Spain.
Nutr Cancer. 2004;50(1):90-100. doi: 10.1207/s15327914nc5001_12.
Flavonoids are polyphenolic phytochemicals that are ubiquitous in plants and present in the common human diet. They may exert diverse beneficial effects, including antioxidant and anticarcinogenic activities. In this study we tested the apoptotic activity of 22 flavonoids and related compounds in leukemic U937 cells. Several flavones but none of the isoflavones or flavanones tested induced apoptotic cell death under these conditions, as determined by reduction in cell viability, flow cytometry, and oligonucleosomal DNA fragmentation. Structure-activity relationship showed that at least two hydroxylations in positions 3, 5, and 7 of the A ring were needed to induce apoptosis, whereas hydroxylation in 3' and/or 4' of the B ring enhanced proapoptotic activity. At lower concentrations, these compounds were also able to sensitize these cells to apoptosis induced by tumor necrosis factor-alpha. Regarding the mechanisms, galangin, luteolin, chrysin, and quercetin induced apoptosis in a way that required the activation of caspases 3 and 8, but not caspase 9. In contrast, an active role of calpains in addition to caspases was demonstrated in apoptosis induced by fisetin, apigenin, and 3,7-dihydroxyflavone. Our data show evidence of the proapoptotic properties of some flavonoids that could support their rational use as chemopreventive and therapeutic agents against carcinogenic disease.
黄酮类化合物是多酚类植物化学物质，广泛存在于植物中，并存在于人类的日常饮食中。它们可能发挥多种有益作用，包括抗氧化和抗癌活性。在本研究中，我们测试了22种黄酮类化合物及相关化合物对白血病U937细胞的凋亡活性。在所测试的条件下，几种黄酮类化合物可诱导凋亡细胞死亡，但异黄酮类或黄烷酮类化合物均无此作用，这是通过细胞活力降低、流式细胞术和寡核小体DNA片段化来确定的。构效关系表明，A环的3、5和7位至少需要两个羟基化才能诱导凋亡，而B环的3'和/或4'位的羟基化则增强促凋亡活性。在较低浓度下，这些化合物还能够使这些细胞对肿瘤坏死因子-α诱导的凋亡敏感。关于其机制，高良姜素、木犀草素、白杨素和槲皮素以需要激活半胱天冬酶3和8，但不需要激活半胱天冬酶9的方式诱导凋亡。相反，在漆黄素、芹菜素和3,7-二羟基黄酮诱导的凋亡中，除了半胱天冬酶外，钙蛋白酶也发挥了积极作用。我们的数据表明一些黄酮类化合物具有促凋亡特性，这可能支持它们作为化学预防和治疗致癌疾病的药物的合理应用。
