RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model

Author(s):Show less -

Ferreira, Adilson Kleber ^[1] ; Tavares, Mauricio Temotheo ^[2] ; Mesquita Pasqualoto, Kerly Fernanda ^[3] ; de Azevedo, Ricardo Alexandre ^[1] ; Teixeira, Sarah Fernandes ^[1] ; Ferreira-Junior, Wilson Alves ^[4] ; Bertin, Ariane Matiello ^[1] ; de-Sa-Junior, Paulo Luiz ^[5] ; Marzago Barbuto, Jose Alexandre ^[6] ; Figueiredo, Carlos Rogerio ^[1] ; Cury, Yara ^[4] ; Costa Bernstorff Damio, Mariana Celestina Frojuello ^[2] ; Parise-Filho, Roberto ^[2]

Affiliation

^[1] Univ Sao Paulo, Dept Immunol, Inst Biomed Sci, Lab Tumor Immunol, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Lab Design & Synth Bioact Subst LAPESSB, Dept Pharm, Fac Pharmaceut Sci, BR-05508000 Sao Paulo, SP - Brazil

^[3] Butantan Inst, Biochem & Biophys Lab, Sao Paulo, SP - Brazil

^[4] Butantan Inst, Lab Pain & Signaling, Sao Paulo, SP - Brazil

^[5] Butantan Inst, Genet Lab, Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Fac Med, Cell & Mol Therapy Ctr NUCEL NETCEM, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: TUMOR BIOLOGY; v. 36, n. 9, p. 7251-7267, SEP 2015.
• Web of Science Citations: 10

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. (AU)

• FAPESP's process: 13/07273-2 - Rational design and development of new prototypes derived of antitumor phospholipids as potential inhibitors of the enzyme CtP: phosphoethanolamine citidililtransferase and antitumor agents in non-small cell lung cancer
• Grantee: Jose Alexandre Marzagão Barbuto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/18160-4 - Novel anticancer candidates: design, synthesis, antitumoral activity and mode of action of novel capsaicinoids and capsinoids analogues
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/23233-8 - Novel anticancer candidates: synthesis and antitumoral activity of capsaicin-like sulfonate and sulfonamide analogues
• Grantee: Maurício Temotheo Tavares
• Support Opportunities: Scholarships in Brazil - Master