Paulo Michel Pinheiro Ferreira1, Denise Barbosa Santos2, Jurandy do Nascimento Silva2, Amanda Freitas Goudinho3, Carla Lorena Silva Ramos2, Patrícia Canteri de Souza4, Ricardo Sérgio Couto de Almeida4, Diego Sousa Moura5, Rhaul de Oliveira5, Cesar Koppe Grisolia5, Alberto José Cavalheiro6, Ana Amélia de Carvalho Melo-Cavalcante7, José Roberto de Oliveira Ferreira8, Manoel Odorico de Moraes Filho9, Claudia Pessoa9. 1. Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Teresina, Brazil; Postgraduate Programs in Pharmaceutical Sciences and Biotechnology, Federal University of Piauí, Teresina, Brazil. Electronic address: pmpf@ufpi.edu.br. 2. Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Teresina, Brazil; Postgraduate Programs in Pharmaceutical Sciences and Biotechnology, Federal University of Piauí, Teresina, Brazil. 3. Department of Biophysics and Physiology, Laboratory of Experimental Cancerology, Federal University of Piauí, Teresina, Brazil. 4. Department of Microbiology, State University of Londrina, Londrina, Brazil. 5. Department of Genetics and Morphology, Institute of Biological Sciences, University of Brasília, Brasília, Brazil. 6. Chemistry Institute, State University Júlio de Mesquita Filho, Araraquara, Brazil. 7. Postgraduate Programs in Pharmaceutical Sciences and Biotechnology, Federal University of Piauí, Teresina, Brazil. 8. School of Medical Sciences, State University of Alagoas, Maceió, Brazil. 9. Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Extracts, essential oils and molecules from Casearia sylvestris have popularly shown pharmacological actions against chronic diseases, as anxiety, inflammation, cancer and dyslipidemia. In the context of antitumoral therapy, we investigated in vitro, ex vivo and in vivo toxicological changes induced by a Fraction with Casearins (FC) and its component Casearin X isolated from C. sylvestris on animal and vegetal cells, and upon invertebrates and mammals. MATERIAL AND METHODS: Cytotoxicity was carried out using normal lines and absorbance and flow cytometry techniques, Artemia salina nauplii, Danio rerio embryos and meristematic cells from Allium cepa roots. Acute and 30 days-mice analysis were done by behavioral, hematological and histological investigations and DNA/chromosomal damages detected by alkaline Cometa and micronucleus assays. RESULTS: FC was cytotoxic against lung and fibroblasts cells and caused DNA breaks, loss of integrity and mitochondrial depolarization on ex vivo human leukocytes. It revealed 24 h-LC50 values of 48.8 and 36.7 μg/mL on A. salina nauplii and D. rerio embryos, reduced mitotic index of A. cepa roots, leading to cell cycle arrest at metaphase and anaphase and micronuclei. FC showed i.p. and oral LD50 values of 80.9 and 267.1 mg/kg body weight. Subacute i.p. injections induced loss of weight, swelling of hepatocytes and tubules, tubular and glomerular hemorrhage, microvesicular steatosis, lung inflammatory infiltration, augment of GPT, decrease of albumin, alkaline phosphatase, glucose, erythrocytes, and lymphocytes, and neutrophilia (p > 0.05). FC-treated animals at 10 mg/kg/day i.p. caused micronuclei in bone marrow and DNA strand breaks in peripheral leukocytes. CONCLUSIONS: This research postulated suggestive side effects after use of FC-related drugs, demonstrating FC as antiproliferative and genotoxic on mammal and meristematic cells, including human leukocytes, teratogenicity upon zebrafish embryos, myelosuppression, clastogenicity, and morphological and biochemical markers indicating liver as main target for FC-induced systemic toxicity.
ETHNOPHARMACOLOGICAL RELEVANCE: Extracts, essential oils and molecules from Casearia sylvestris have popularly shown pharmacological actions against chronic diseases, as anxiety, inflammation, cancer and dyslipidemia. In the context of antitumoral therapy, we investigated in vitro, ex vivo and in vivo toxicological changes induced by a Fraction with Casearins (FC) and its component Casearin X isolated from C. sylvestris on animal and vegetal cells, and upon invertebrates and mammals. MATERIAL AND METHODS:Cytotoxicity was carried out using normal lines and absorbance and flow cytometry techniques, Artemia salina nauplii, Danio rerio embryos and meristematic cells from Allium cepa roots. Acute and 30 days-mice analysis were done by behavioral, hematological and histological investigations and DNA/chromosomal damages detected by alkaline Cometa and micronucleus assays. RESULTS:FC was cytotoxic against lung and fibroblasts cells and caused DNA breaks, loss of integrity and mitochondrial depolarization on ex vivo human leukocytes. It revealed 24 h-LC50 values of 48.8 and 36.7 μg/mL on A. salina nauplii and D. rerio embryos, reduced mitotic index of A. cepa roots, leading to cell cycle arrest at metaphase and anaphase and micronuclei. FC showed i.p. and oral LD50 values of 80.9 and 267.1 mg/kg body weight. Subacute i.p. injections induced loss of weight, swelling of hepatocytes and tubules, tubular and glomerular hemorrhage, microvesicular steatosis, lung inflammatory infiltration, augment of GPT, decrease of albumin, alkaline phosphatase, glucose, erythrocytes, and lymphocytes, and neutrophilia (p > 0.05). FC-treated animals at 10 mg/kg/day i.p. caused micronuclei in bone marrow and DNA strand breaks in peripheral leukocytes. CONCLUSIONS: This research postulated suggestive side effects after use of FC-related drugs, demonstrating FC as antiproliferative and genotoxic on mammal and meristematic cells, including human leukocytes, teratogenicity upon zebrafish embryos, myelosuppression, clastogenicity, and morphological and biochemical markers indicating liver as main target for FC-induced systemic toxicity.
Authors: Paulo Michel Pinheiro Ferreira; Renata Rosado Drumond; Jurandy do Nascimento Silva; Ian Jhemes Oliveira Sousa; Marcus Vinicius Oliveira Barros de Alencar; Ana Maria Oliveira Ferreira da Mata; Nayana Bruna Nery Monção; Antonia Maria das Graças Lopes Citó; Ana Fontenele Urano Carvalho; Davi Felipe Farias; Patrícia Marçal da Costa; Adriana Maria Viana Nunes; João Marcelo de Castro E Sousa; Ana Amélia de Carvalho Melo-Cavalcante Journal: J Oncol Date: 2021-12-07 Impact factor: 4.375
Authors: Sabrina M Ribeiro; Érick D O Fratucelli; Paula C P Bueno; Marlene Kelly V de Castro; Amanda Alcalá Francisco; Alberto José Cavalheiro; Marlise I Klein Journal: BMC Complement Altern Med Date: 2019-11-12 Impact factor: 3.659