Department of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556, Wrocław, Poland.
Department of Organic Chemistry, Wroclaw Medical University, Wrocław, Poland.
Pharmacol Rep. 2020 Feb;72(1):214-224. doi: 10.1007/s43440-019-00004-1. Epub 2020 Jan 8.
The p53 protein is a transcription factor for many genes, including genes involved in inhibiting cell proliferation and inducing apoptosis in genotoxically damaged and tumor-transformed cells. In more than 55% of cases of human cancers, loss of the essential function of p53 protein is found. In numerous reports, it has been shown that small molecules (chemical compounds) can restore the suppressor function of the mutant p53 protein in tumor cells. The aim of this study was to evaluate the potential anticancer activity of three newly synthesized olivacine derivatives.
The study was performed using two cell lines-CCRF/CEM (containing the mutant p53 protein) and A549 (containing a non-mutant, wild-type p53 protein). The cells were incubated with olivacine derivatives for 18 h and then assays were carried out: measurement of the amount of p53 and p21 proteins, detection of apoptosis, cell cycle analysis, and rhodamine 123 accumulation assay (evaluation of P-glycoprotein inhibition). Multiple-criteria decision analysis was used to compare the anticancer activity of the tested compounds.
Each tested compound caused the reconstitution of suppressor activity of the p53 protein in cells with the mutant protein. In addition, one of the compounds showed significant antitumor activity in both wild-type and mutant cells. For all compounds, a stronger effect on the level of the p53 protein was observed than for the reference compound-ellipticine.
The observed effects of the tested new olivacine derivatives (pyridocarbazoles) suggest that they are good candidates for new anticancer drugs.
p53 蛋白是许多基因的转录因子，包括参与抑制细胞增殖和诱导基因毒性损伤和肿瘤转化细胞凋亡的基因。在超过 55%的人类癌症病例中，发现 p53 蛋白的必需功能丧失。在众多报告中，已经表明小分子（化学化合物）可以恢复肿瘤细胞中突变型 p53 蛋白的抑制功能。本研究旨在评估三种新合成的橄榄苦苷衍生物的潜在抗癌活性。
该研究使用两种细胞系-CCRF/CEM（含有突变型 p53 蛋白）和 A549（含有非突变型、野生型 p53 蛋白）进行。将细胞与橄榄苦苷衍生物孵育 18 小时，然后进行以下测定：p53 和 p21 蛋白的量的测量、凋亡的检测、细胞周期分析和罗丹明 123 积累测定（评估 P-糖蛋白抑制）。多标准决策分析用于比较测试化合物的抗癌活性。
每种测试的化合物都导致具有突变蛋白的细胞中 p53 蛋白抑制活性的重建。此外，一种化合物在野生型和突变细胞中均表现出显著的抗肿瘤活性。对于所有化合物，与参比化合物-椭圆体素相比，观察到对 p53 蛋白水平的更强作用。
所观察到的测试新橄榄苦苷衍生物（吡啶并咔唑）的作用表明它们是新型抗癌药物的良好候选物。
