de Abrantes Renata A, Batista Tatianne M, Mangueira Vivianne M, de Sousa Tatyanna K G, Ferreira Rafael C, Moura Ana Paula G, Abreu Lucas S, Alves Adriano F, Velozo Eudes S, Batista Leônia M, da Silva Marcelo S, Tavares Josean F, Sobral Marianna V
Post Graduation Program in Bioactive Natural and Synthetic Products, Federal University of Paraíba, João Pessoa, Brazil.
Department of Physiology and Pathology, Federal University of Paraíba, João Pessoa, PB, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2022 Feb;395(2):267-274. doi: 10.1007/s00210-021-02185-0. Epub 2021 Dec 2.
Natural products have played a pivotal role for the discovery of anticancer drugs. Tonantzitlolones are flexibilan-type diterpenes rare in nature; therefore, few reports have shown antiviral and cytotoxic activities. This study aimed to investigate the in vivo antitumor action of Tonantzitlolone B (TNZ-B) and its toxicity. Toxicity was evaluated in mice (acute and micronucleus assays). Antitumor activity of TNZ-B (1.5 or 3 mg/kg intraperitoneally - i.p.) was assessed in Ehrlich ascites carcinoma model. Angiogenesis and reactive oxygen species (ROS) and nitric oxide (NO) production were also investigated, in addition to toxicological effects after 7-day treatment. The LD (lethal dose 50%) was estimated at around 25 mg/kg (i.p.), and no genotoxicity was recorded. TNZ-B reduced the Ehrlich tumor's volume and total viable cancer cell count (p < 0.001 for both). Additionally, TNZ-B reduced peritumoral microvessel density (p < 0.01), suggesting antiangiogenic action. Moreover, a decrease was observed on ROS (p < 0.05) and nitric oxide (p < 0.001) levels. No significant clinical findings were observed in the analysis of biochemical, hematological, and histological (liver and kidney) parameters. In conclusion, TNZ-B exerts antitumor and antiangiogenic effects by reducing ROS and NO levels and has weak in vivo dose-repeated toxicity. These data contribute to elucidate the antitumor action of TNZ-B and point the way for further studies with this natural compound as an anticancer drug.
天然产物在抗癌药物的发现中发挥了关键作用。托南齐特洛酮是自然界中罕见的柔韧性二萜类化合物；因此，很少有报道显示其具有抗病毒和细胞毒性活性。本研究旨在探讨托南齐特洛酮B（TNZ-B）的体内抗肿瘤作用及其毒性。在小鼠中评估毒性（急性和微核试验）。在艾氏腹水癌模型中评估TNZ-B（腹腔注射1.5或3mg/kg）的抗肿瘤活性。除了7天治疗后的毒理学效应外，还研究了血管生成、活性氧（ROS）和一氧化氮（NO）的产生。估计半数致死剂量（LD50%）约为25mg/kg（腹腔注射），未记录到遗传毒性。TNZ-B减小了艾氏肿瘤的体积和总存活癌细胞计数（两者均p<0.001）。此外，TNZ-B降低了肿瘤周围微血管密度（p<0.01），表明其具有抗血管生成作用。此外，观察到ROS（p<0.05）和一氧化氮（p<0.001）水平降低。在生化、血液学和组织学（肝脏和肾脏）参数分析中未观察到明显的临床发现。总之，TNZ-B通过降低ROS和NO水平发挥抗肿瘤和抗血管生成作用，且体内重复给药毒性较弱。这些数据有助于阐明TNZ-B的抗肿瘤作用，并为进一步研究这种天然化合物作为抗癌药物指明方向。
