1. Antitumor and antiangiogenic effects of Tonantzitlolone B, an uncommon diterpene from Stillingia loranthacea.
- Author
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de Abrantes RA, Batista TM, Mangueira VM, de Sousa TKG, Ferreira RC, Moura APG, Abreu LS, Alves AF, Velozo ES, Batista LM, da Silva MS, Tavares JF, and Sobral MV
- Subjects
- Angiogenesis Inhibitors administration & dosage, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors toxicity, Animals, Antineoplastic Agents, Phytogenic administration & dosage, Antineoplastic Agents, Phytogenic toxicity, Cell Line, Tumor, Diterpenes administration & dosage, Diterpenes toxicity, Dose-Response Relationship, Drug, Female, Lethal Dose 50, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds toxicity, Mice, Micronucleus Tests, Nitric Oxide metabolism, Reactive Oxygen Species metabolism, Antineoplastic Agents, Phytogenic pharmacology, Carcinoma, Ehrlich Tumor drug therapy, Diterpenes pharmacology, Euphorbiaceae chemistry, Macrocyclic Compounds pharmacology
- Abstract
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
50 (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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2022
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