AUTHOR=Lacerda Pammela A. , Oenning Luan C. , Bellato Guilherme Cuoghi , Lopes-Santos Lucilene , Antunes Natalícia de Jesus , Mariz Bruno Augusto Linhares Almeida , Teixeira Gabriela , Vasconcelos Rafael , Simões Gustavo Ferreira , de Souza Ivani Aparecida , Pinto Clóvis Antônio Lopes , Salo Tuula , Coletta Ricardo D. , Augusto Taize M. , de Oliveira Carine Ervolino , Cervigne Nilva K. 

TITLE=Polypodium leucotomos targets multiple aspects of oral carcinogenesis and it is a potential antitumor phytotherapy against tongue cancer growth

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1098374

DOI=10.3389/fphar.2022.1098374

ISSN=1663-9812

ABSTRACT=Oral cancer refers to malignant tumors, of which 90% are squamous cell carcinomas (OSCCs). These malignancies exhibit rapid progression, poor prognosis, and often mutilating therapeutical approaches. The determination of a prophylactic and/or therapeutic antitumor role of the polyphenolic extract Polypodium leucotomos(PL) would be relevant in developing new tools for prevention and treatment. In the present study, we aimed to determine the antitumor effect of PL by treating OSCC cell lines with PL metabolites and evaluating its action during OSCC progression in vivo. PL treatment successfully impaired cell cycling and proliferation, migration, and invasion, enhanced apoptosis, and modulated macrophage polarization associated with the tumoral immune-inflammatory response of tongue cancer cell lines (TSCC).  PL treatment significantly decreased the expression of MMP1 (p<0.01) and MMP2 (p<0.001), and increased the expression of TIMP1 (p<0.001) and TIMP2 (p<0.0001) in these cells. The mesenchymal-epithelium transition (MET) phenotype was promoted in cells treated with PL,  through upregulation of E-CAD (p<0.001) and reduction of N-CAD (p<0.05). In vivo experiments, carried out by 4-nitroquinolina-1-óxido (4-NQO)-inducted TSCCs, showed that PL restrained OSCC progression, by inhibiting tumor volume growth and decreasing the number of severe dysplasia lesions and TSCCs. Ki-67 was significantly higher expressed in tongue tissues of animals not treated with PL(p<0.05), and a notable reduction in Bcl2(p<0.05) and Pcna(p<0.05) cell proliferation-associated genes was found in dysplastic lesions and TSCCs of treated mice. Finally, N-cad(Cdh2), Vim, and Twist were significantly reduced in tongue tissues treated with PL. In conclusion, PL significantly decreased OSCC carcinogenic processes in vitro and inhibited tumor progression in vivo. In addition, PL appears to contribute to the modulation of immune-inflammatory oral tumor-associated responses. Taken together, these results suggest that PL plays an important antitumor role in processes associated with oral carcinogenesis and may be a potential phytotherapeutic target for the prevention and/or adjuvant treatment of TSCCs.