Toxic profile of marinobufagin from poisonous Amazon toads and antitumoral effects on human colorectal carcinomas

• Published in: Journal of ethnopharmacology 2023-06, Vol.310, p.116406-116406, Article 116406
• Main Authors: Ferreira, Paulo Michel Pinheiro, Sousa, Lívia Queiroz de, Sousa, Rayran Walter Ramos de, Rodrigues, Domingos de Jesus, Monção Filho, Evaldo dos Santos, Chaves, Mariana Helena, Vieira Júnior, Gerardo Magela, Rizzo, Márcia dos Santos, Filgueiras, Lívia Alves, Mendes, Anderson Nogueira, Lima, Daisy Jereissati Barbosa, Pessoa, Cláudia, Sousa, João Marcelo de Castro e, Rodrigues, Ana Carolina Borges da Cruz, Soares, Milena Botelho Pereira, Bezerra, Daniel Pereira
• Format: Article
• Language: English
• Subjects: acute exposure; acute toxicity; Animals; Ataxia; blood; bone marrow; Bufadienolides; Bufonidae; Cardenolides; colorectal neoplasms; Colorectal Neoplasms - drug therapy; computer simulation; creatinine; cytogenetics; cytotoxicity; Daphnia; death; ecotoxicology; gastrointestinal system; gastrointestinal transit; Histological analyses; histopathology; Humans; Mammals; Mice; Mice, SCID; Murine cells; Oryzias latipes; ouabain; Pharmacological safety; Pimephales promelas; Poisons; sarcoma; Sarcoma 180; toads; traditional medicine; urea; Xenograft model; xenotransplantation
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2023.116406

South Americans natives have extensively used the toad “kururu” to reduce/treat skin infections, cutaneous lesions and sores. They release secretions rich in bufadienolides, polyhydroxy steroids with well-documented cardiotonic and antiproliferative actions, but in vivo antitumoral evaluations in mammals are rare, and toxicological safety has been left in second place. This investigation used in silico, in vitro and in vivo tools to evaluate acute and subacute toxic effects of marinobufagin and the anticancer action in tumor-bearing mice models. Initially, in silico toxic predictions were performed, followed by in vitro assays using human and murine normal and tumor lines. Next, acute and subacute studies on mice investigated the behavior, hematological and intestinal transit profile and antitumoral activity of marinobufagin in sarcoma 180- and HCT-116 colorectal carcinoma-transplanted mice for 7 and 15 days, respectively. Ex vivo and in vivo cytogenetic assays in Sarcoma 180 and bone marrow cells and histopathological examinations were also executed. In silico studies revealed ecotoxicological effects on crustaceans (Daphnia sp.), fishes (Pimephales promelas and Oryzias latipes), and algae. A 24-h marinobufagin-induced acute toxicity included signals of central activity, mainly (vocal frenzy, absence of body tonus, increased ventilation, ataxia, and equilibrium loss), and convulsions and death at 10 mg/kg. The bufadienolide presented effective in vitro cytotoxic action on human lines of colorectal carcinomas in a similar way to ouabain and tumor reduction in marinobufagin-treated SCID-bearing HCT-116 heterotopic xenografts. Animals under subacute nonlethal doses exhibited a decrease in creatinine clearance with normal levels of blood urea, probably as a result of a marinobufagin-induced renal perfusion fall. Nevertheless, only minor morphological side effects were identified in kidneys, livers, hearts and lungs. Marinobufagin has in vitro and in vivo anticancer action on colorectal carcinoma and mild and reversible alterations in key metabolic organs without direct chemotherapy-induced gastrointestinal effects at subacute exposure, but it causes acute ataxia, equilibrium loss, convulsions and death at higher acute exposure. [Display omitted] •In silico ecotoxicity of marinobufagin on crustaceans, fishes, and algae.•In vitro cytotoxicity similar to ouabain upon human lines of colorectal carcinomas.•24-h acute toxicity includes ataxia, with convulsions and