title: RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model.
abstract: Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analogue of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthetized, and molecular modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis, by flow cytometry, and Western blot analysis of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The production of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico analysis corroborated the biological findings, showing that RPF151 has physicochemical improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy.
authors.affiliation: Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil. ferreira-kleber@usp.br.
authors.forename: Adilson Kleber
authors.initials: AK
authors.lastname: Ferreira
authors.affiliation: Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, 05508-000, São Paulo, SP, Brazil.
authors.forename: Maurício Temotheo
authors.initials: MT
authors.lastname: Tavares
authors.affiliation: Biochemistry and Biophysical Laboratory, Butantan Institute, São Paulo, SP, Brazil.
authors.forename: Kerly Fernanda Mesquita
authors.initials: KF
authors.lastname: Pasqualoto
authors.affiliation: Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil.
authors.forename: Ricardo Alexandre
authors.initials: RA
authors.lastname: de Azevedo
authors.affiliation: Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil.
authors.forename: Sarah Fernandes
authors.initials: SF
authors.lastname: Teixeira
authors.affiliation: Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, Brazil.
authors.forename: Wilson Alves
authors.initials: WA
authors.lastname: Ferreira-Junior
authors.affiliation: Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil.
authors.forename: Ariane Matiello
authors.initials: AM
authors.lastname: Bertin
authors.affiliation: Laboratory of Genetics, Butantan Institute, São Paulo, SP, Brazil.
authors.forename: Paulo Luiz
authors.initials: PL
authors.lastname: de-Sá-Junior
authors.affiliation: Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil.|Cell and Molecular Therapy Center NUCEL/NETCEM, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: José Alexandre Marzagão
authors.initials: JA
authors.lastname: Barbuto
authors.affiliation: Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, SP, Brazil.
authors.forename: Carlos Rogério
authors.initials: CR
authors.lastname: Figueiredo
authors.affiliation: Laboratory of Pain and Signaling, Butantan Institute, São Paulo, SP, Brazil.
authors.forename: Yara
authors.initials: Y
authors.lastname: Cury
authors.affiliation: Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, 05508-000, São Paulo, SP, Brazil.
authors.forename: Mariana Celestina Frojuello Costa Bernstorff
authors.initials: MC
authors.lastname: Damião
authors.affiliation: Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Prof. Lineu Prestes Avenue, 580, 05508-000, São Paulo, SP, Brazil. roberto.parise@usp.br.
authors.forename: Roberto
authors.initials: R
authors.lastname: Parise-Filho
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002211:Capsaicin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D002211:Capsaicin
keywords: Alkyl sulfonamide analogue; Antitumor; Apoptosis; Capsaicin; MDA-MB-231; RPF151