State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
Invest New Drugs. 2011 Dec;29(6):1230-40. doi: 10.1007/s10637-010-9468-5. Epub 2010 Jun 26.
To explore the potential anti-tumour activities of xanthone derivatives, 26 hydroxylxanthones and benzoxanthones and their structurally modified analogues were examined for potential cytotoxic activities against eight human cancer cell lines. Most of the xanthone derivatives exhibited a higher degree of cytotoxicity on HepG2 cells than on the other seven cancer cell lines. Compound 24 (1,3,7-Trihydroxy-12H-benzo[b] xanthen-12-one) showed the highest degree of cytotoxicity of the tested compounds against HepG2 cells and demonstrated good tumour specificity by exhibiting a much higher degree of cytotoxicity against HepG2 cells than against normal liver cells (L02). Several valuable structure-activity relationships were derived from the cytotoxicity data. In addition, we found that compound 24 could downregulate the expression of the Mcl-1 protein, induce changes in the mitochondrial membrane potential and induce apoptosis in HepG2 cells via the mitochondrial pathway. Compound 24 was also shown to inhibit topoisomerase (topo) II activity and downregulate the levels of both topo II mRNA and protein in HepG2 cells. The present results suggest that due to its potent cytotoxicity and good tumour selectivity, compound 24 may be exploited as a potential lead compound in the development of a new anti-tumour agent with specific activity against liver cancer.
为了探索黄烷酮衍生物的潜在抗肿瘤活性，对 26 种羟基黄烷酮和苯并黄烷酮及其结构修饰类似物进行了研究，以评估它们对八种人癌细胞系的潜在细胞毒性活性。大多数黄烷酮衍生物对 HepG2 细胞的细胞毒性程度高于对其他七种癌细胞系的细胞毒性程度。化合物 24（1,3,7-三羟基-12H-苯并[b]黄烷-12-酮）对 HepG2 细胞的细胞毒性最强，对 HepG2 细胞的细胞毒性比对正常肝细胞（L02）的细胞毒性高得多，表现出良好的肿瘤特异性。从细胞毒性数据中得出了一些有价值的构效关系。此外，我们发现化合物 24 可以通过线粒体途径下调 Mcl-1 蛋白的表达，改变线粒体膜电位，并诱导 HepG2 细胞凋亡。化合物 24 还被证明可以抑制拓扑异构酶（topo）II 活性，并下调 HepG2 细胞中 topo II mRNA 和蛋白的水平。这些结果表明，由于其强大的细胞毒性和良好的肿瘤选择性，化合物 24 可能被开发为一种具有特异性抗肝癌活性的新型抗肿瘤药物的潜在先导化合物。
