García-Niño W R, Estrada-Muñiz E, Valverde M, Reyes-Chilpa R, Vega L
Department of Toxicology, Centre for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Av. IPN 2508, San Pedro Zacatenco, GA Madero, Ciudad de México, CP 07360, Mexico.
Department of Genomic Medicine and Environmental Toxicology, Biomedical Research Institute, National University of Mexico (UNAM), Ciudad de México, CP 04510, Mexico.
Toxicol Appl Pharmacol. 2017 Nov 15;335:6-15. doi: 10.1016/j.taap.2017.09.018. Epub 2017 Sep 22.
Jacareubin is a xanthone isolated from the heartwood of Calophyllum brasiliense with antibacterial and gastroprotective properties and the intention for clinical use as an anti-cancer treatment (due to the similar chemical structure to other anti-neoplastic drugs) requires an investigation of whether this compound can generate adverse effects on non-transformed cells. Jacareubin (0.5-1000μM in DMSO) was more cytotoxic on phytohemagglutinin (PHA)-stimulated normal human peripheral blood mononuclear cells (PBMCs; IC at 72h by MTT: 85.9μM) than on G phase-PBMCs (IC 315.6μM) using trypan blue exclusion and formazan metabolism assays. Jacareubin had lower toxicity on PBMCs than Taxol (1μM). Jacareubin presented cytostatic activity because it inhibited PHA-stimulated PBMCs proliferation (from 2.5μM; CFSE dilution and replication index). Jacareubin induced PBMCs arrest in G/G phase of the cell cycle (from 5μM) as evaluated by DNA content. Moreover, Jacareubin generated genotoxicity by breaking DNA strands selectively in PHA-stimulated PBMCs (from 5μM) rather than on resting PBMCs using the single-cell gel electrophoresis assay and increasing the frequency of micronucleated (MN) PBMCs in vitro (from 5μM) and frequency of hypodiploid cells (from 10μM). When 100mg/kg Jacareubin was injected i.p. into mice (a fifth of the LD; 0.548g/kg. Approximately to 300μM in vitro), we observe no increase in the MN level in bone marrow cells. Jacareubin can be consider for further anti-tumoural activity due to its preferential genotoxic, cytotoxic and cytostatic actions on proliferating cells rather than on resting cells and the lack of in vivo genotoxicity.
巴西红厚壳素是从巴西红厚壳的心材中分离出的一种呫吨酮，具有抗菌和胃保护特性，由于其化学结构与其他抗肿瘤药物相似，因此作为抗癌治疗药物用于临床需要研究该化合物是否会对未转化细胞产生不良反应。采用台盼蓝排斥法和甲臜代谢试验，巴西红厚壳素（在二甲基亚砜中的浓度为0.5 - 1000μM）对植物血凝素（PHA）刺激的正常人外周血单个核细胞（PBMCs；MTT法测定72小时的IC：85.9μM）的细胞毒性比对G期PBMCs（IC 315.6μM）更大。巴西红厚壳素对PBMCs的毒性低于紫杉醇（1μM）。巴西红厚壳素具有细胞生长抑制活性，因为它抑制PHA刺激的PBMCs增殖（从2.5μM起；羧基荧光素琥珀酰亚胺酯稀释和复制指数）。通过DNA含量评估，巴西红厚壳素（从5μM起）诱导PBMCs停滞在细胞周期的G/G期。此外，使用单细胞凝胶电泳试验，巴西红厚壳素（从5μM起）在PHA刺激的PBMCs中选择性地断裂DNA链，从而产生遗传毒性，而对静息的PBMCs则无此作用，并且在体外增加了微核化（MN）PBMCs的频率（从5μM起）以及亚二倍体细胞的频率（从10μM起）。当将100mg/kg巴西红厚壳素腹腔注射到小鼠体内（LD的五分之一；0.548g/kg，体外约为300μM）时，我们观察到骨髓细胞中的MN水平没有增加。由于巴西红厚壳素对增殖细胞而非静息细胞具有优先的遗传毒性、细胞毒性和细胞生长抑制作用，并且缺乏体内遗传毒性，因此可以考虑其进一步的抗肿瘤活性。
