Anticancer Activity and Molecular Targets of <i>Piper cernuum</i> Substances in Oral Squamous Cell Carcinoma Models
Thaíssa Queiróz Machado,
Maria Emanuelle Damazio Lima,
Rafael Carriello da Silva,
Arthur Ladeira Macedo,
Lucas Nicolau de Queiroz,
Bianca Roberta Peres Angrisani,
Anna Carolina Carvalho da Fonseca,
Priscilla Rodrigues Câmara,
Vitor Von-Held Rabelo,
Carlos Alexandre Carollo,
Davyson de Lima Moreira,
Elan Cardozo Paes de Almeida,
Thatyana Rocha Alves Vasconcelos,
Paula Alvarez Abreu,
Alessandra Leda Valverde,
Bruno Kaufmann Robbs
Affiliations
Thaíssa Queiróz Machado
Postgraduate Program in Applied Science for Health Products, Faculty of Pharmacy, Fluminense Federal University, Niteroi 24241-000, RJ, Brazil
Maria Emanuelle Damazio Lima
Department of Organic Chemistry, Chemistry Institute, Fluminense Federal University, Niteroi 24020-141, RJ, Brazil
Rafael Carriello da Silva
Postgraduate Program in Dentistry, Health Institute of Nova Friburgo, Fluminense Federal University, Nova Friburgo 28625-650, RJ, Brazil
Arthur Ladeira Macedo
Pharmaceutical Sciences, Food and Nutrition Faculty, Mato Grosso do Sul Federal University, Campo Grande 79070-900, MS, Brazil
Lucas Nicolau de Queiroz
Postgraduate Program in Applied Science for Health Products, Faculty of Pharmacy, Fluminense Federal University, Niteroi 24241-000, RJ, Brazil
Bianca Roberta Peres Angrisani
Department of Organic Chemistry, Chemistry Institute, Fluminense Federal University, Niteroi 24020-141, RJ, Brazil
Anna Carolina Carvalho da Fonseca
Postgraduate Program in Dentistry, Health Institute of Nova Friburgo, Fluminense Federal University, Nova Friburgo 28625-650, RJ, Brazil
Priscilla Rodrigues Câmara
Basic Science Department, Health Institute of Nova Friburgo, Fluminense Federal University, Nova Friburgo 28625-650, RJ, Brazil
Vitor Von-Held Rabelo
Biodiversity and Sustainability Institute, Macaé Campus, Federal University of Rio de Janeiro, Macae 21941-901, RJ, Brazil
Carlos Alexandre Carollo
Pharmaceutical Sciences, Food and Nutrition Faculty, Mato Grosso do Sul Federal University, Campo Grande 79070-900, MS, Brazil
Davyson de Lima Moreira
Research Directorate, Laboratory of Natural Products and Biochemistry, Rio de Janeiro Botanical Garden Research Institute, Rio de Janeiro 22460-030, RJ, Brazil
Elan Cardozo Paes de Almeida
Basic Science Department, Health Institute of Nova Friburgo, Fluminense Federal University, Nova Friburgo 28625-650, RJ, Brazil
Thatyana Rocha Alves Vasconcelos
Department of Organic Chemistry, Chemistry Institute, Fluminense Federal University, Niteroi 24020-141, RJ, Brazil
Paula Alvarez Abreu
Biodiversity and Sustainability Institute, Macaé Campus, Federal University of Rio de Janeiro, Macae 21941-901, RJ, Brazil
Alessandra Leda Valverde
Department of Organic Chemistry, Chemistry Institute, Fluminense Federal University, Niteroi 24020-141, RJ, Brazil
Bruno Kaufmann Robbs
Basic Science Department, Health Institute of Nova Friburgo, Fluminense Federal University, Nova Friburgo 28625-650, RJ, Brazil
Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. Piper plant species have shown many biological activities. In the present study, we show that dichloromethane partition of Piper cernuum (PCLd) is nontoxic in chronic treatment in mice, reduces the amount of atypia in tongues of chemically induced OSCC, and significantly increases animal survival. To identify the main active compounds, chromatographic purification of PCLd was performed, where fractions 09.07 and 14.05 were the most active and selective. These fractions promoted cell death by apoptosis characterized by phosphatidyl serine exposition, DNA fragmentation, and activation of effector caspase-3/7 and were nonhemolytic. LC–DAD–MS/MS analysis did not propose matching spectra for the 09.07 fraction, suggesting compounds not yet known. However, aporphine alkaloids were annotated in fraction 14.05, which are being described for the first time in P. cernuum and corroborate the observed cytotoxic activity. Putative molecular targets were determined for these alkaloids, in silico, where the androgen receptor (AR), CHK1, CK2, DYRK1A, EHMT2, LXRβ, and VEGFR2 were the most relevant. The results obtained from P. cernuum fractions point to promising compounds as new preclinical anticancer candidates.
