Tumor Biology

, Volume 36, Issue 9, pp 7251–7267 | Cite as

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

  • Adilson Kleber Ferreira
  • Maurício Temotheo Tavares
  • Kerly Fernanda Mesquita Pasqualoto
  • Ricardo Alexandre de Azevedo
  • Sarah Fernandes Teixeira
  • Wilson Alves Ferreira-Junior
  • Ariane Matiello Bertin
  • Paulo Luiz de-Sá-Junior
  • José Alexandre Marzagão Barbuto
  • Carlos Rogério Figueiredo
  • Yara Cury
  • Mariana Celestina Frojuello Costa Bernstorff Damião
  • Roberto Parise-Filho
Research Article

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.

Keywords

Alkyl sulfonamide analogue RPF151 Antitumor Apoptosis Capsaicin MDA-MB-231 

Notes

Acknowledgments

This work was supported by grants of the Provost’s Office for Research of University of Sao Paulo, CAPES and CNPq (Brazil). The authors are grateful to FAPESP (proc. nr.: 2012/23233-8, 2013/18160-4, and 2013/07273-2) and to Professor Leoberto Costa Tavares, coordinator of Laboratory for Designing and Development of New Drugs, Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmacy at University of Sao Paulo, who kindly allowed the use of a workstation to perform the in silico analysis, and to the Chem21 Group, Inc., for the MOLSIM 3.2 software academic license.

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Adilson Kleber Ferreira
    • 1
  • Maurício Temotheo Tavares
    • 2
  • Kerly Fernanda Mesquita Pasqualoto
    • 3
  • Ricardo Alexandre de Azevedo
    • 1
  • Sarah Fernandes Teixeira
    • 1
  • Wilson Alves Ferreira-Junior
    • 4
  • Ariane Matiello Bertin
    • 1
  • Paulo Luiz de-Sá-Junior
    • 5
  • José Alexandre Marzagão Barbuto
    • 1
    • 6
  • Carlos Rogério Figueiredo
    • 1
  • Yara Cury
    • 4
  • Mariana Celestina Frojuello Costa Bernstorff Damião
    • 2
  • Roberto Parise-Filho
    • 2
  1. 1.Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical SciencesUniversity of Sao PauloSão PauloBrazil
  2. 2.Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical SciencesUniversity of Sao PauloSão PauloBrazil
  3. 3.Biochemistry and Biophysical LaboratoryButantan InstituteSão PauloBrazil
  4. 4.Laboratory of Pain and SignalingButantan InstituteSão PauloBrazil
  5. 5.Laboratory of GeneticsButantan InstituteSão PauloBrazil
  6. 6.Cell and Molecular Therapy Center NUCEL/NETCEM, Faculty of MedicineUniversity of São PauloSão PauloBrazil

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