PDF herunterladen
Planta Med 2023; 89(02): 158-167
DOI: 10.1055/a-1890-5446
Biological and Pharmacological Activity
Original Papers

Guttiferone E Displays Antineoplastic Activity Against Melanoma Cells

Arthur Barcelos Ribeiro
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
,
Heloiza Diniz Nicolella
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
,
Lucas Henrique Domingos da Silva 
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
,
Jennyfer Andrea Aldana Mejía
2   School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
Matheus Hikaru Tanimoto
2   School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
Sérgio Ricardo Ambrósio
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
,
Jairo Kenupp Bastos
2   School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
,
Renato Pereira Orenha
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
,
Renato Luis Tame Parreira
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
,
Denise Crispim Tavares 
1   University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil
› InstitutsangabenGefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo #2017/04138-8
Gefördert durch: Fundação de Amparo à Pesquisa do Estado de São Paulo #2018/25770-7
› Weitere Informationen
Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Guttiferone E (GE) is a benzophenone found in Brazilian red propolis. In the present study, the effect of GE on human (A-375) and murine (B16-F10) melanoma cells was investigated. GE significantly reduced the cellular viability of melanoma cells in a time-dependent manner. In addition, GE demonstrated antiproliferative effect, with IC50 values equivalent to 9.0 and 6.6 µM for A-375 and B16-F10 cells, respectively. The treatment of A-375 cells with GE significantly increased cell populations in G0/G1 phase and decreased those in G2/M phase. Conversely, on B16-F10 cells, GE led to a significant decrease in the populations of cells in G0/G1 phase and concomitantly an increase in the population of cells in phase S. A significantly higher percentage of apoptotic cells was observed in A-375 (43.5%) and B16-F10 (49.9%) cultures after treatment with GE. Treatments with GE caused morphological changes and significant decrease to the melanoma cellsʼ density. GE (10 µM) inhibited the migration of melanoma cells, with a higher rate of inhibition in B16-F10 cells (73.4%) observed. In addition, GE significantly reduced the adhesion of A375 cells, but showed no effect on B16-F10. Treatment with GE did not induce changes in P53 levels in A375 cultures. Molecular docking calculations showed that GE is stable in the active sites of the tubulin dimer with a similar energy to taxol chemotherapy. Taken together, the data suggest that GE has promising antineoplastic potential against melanoma.

Key words

Benzophenone - Brazilian red propolis - cell cycle - apoptosis - P53

Supporting Information

    The DNA content profile of cell cycle analyses; apoptosis profile of cell death evaluation and Western blot analysis of p53 expression are available in the Supporting Information.

  • Ergänzendes Material


Publikationsverlauf

Eingereicht: 28. Januar 2022

Angenommen nach Revision: 10. Juni 2022

Artikel online veröffentlicht:
28. September 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ahmed F, Haass NK. Microenvironment-driven dynamic heterogeneity and phenotypic plasticity as a mechanism of melanoma therapy resistance. Front Oncol 2018; 8: 1-7
    CrossrefPubMedSuche in Google Scholar
  • 2 Grimes JM, Shah NV, Samie FH, Carvajal RD, Marr BP. Conjunctival MELANOMA: Current treatments and future options. Am J Clin Dermatol 2020; 21: 371-381
    CrossrefPubMedSuche in Google Scholar
  • 3 Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020; 83: 770-803
    Suche in Google Scholar
  • 4 Wu SB, Long C, Kennelly EJ. Structural diversity and bioactivities of natural benzophenones. Nat Prod Rep 2014; 31: 1158-1174
    CrossrefPubMedSuche in Google Scholar
  • 5 Surana K, Chaudhary B, Diwaker M, Sharma S. Benzophenone: A ubiquitous scaffold in medicinal chemistry. Medchemcomm 2018; 9: 1803-1817
    CrossrefPubMedSuche in Google Scholar
  • 6 Ccana-Ccapatinta GV, Mejía JAA, Tanimoto MH, Groppo M, Carvalho JCAS, Bastos JK. Dalbergia ecastaphyllum (L.) Taub. and Symphonia globulifera L.f.: The botanical sources of isoflavonoids and benzophenones in Brazilian red propolis. Molecules 2020; 25: 2060-2067
    CrossrefPubMedSuche in Google Scholar
  • 7 López BG, Schmidt EM, Eberlin MN, Sawaya AC. Phytochemical markers of different types of red propolis. Food Chem 2014; 146: 174-180
    CrossrefPubMedSuche in Google Scholar
  • 8 Fasolo D, Bergold AM, von Poser G, Teixeira HF. Determination of benzophenones in lipophilic extract of Brazilian red propolis, nanotechnology-based product and porcine skin and mucosa: Analytical and bioanalytical assays. J Pharm Biomed Anal 2016; 124: 57-66
    CrossrefPubMedSuche in Google Scholar
  • 9 Protiva P, Hopkins ME, Baggett S, Yang H, Lipkin M, Holt PR, Kennelly EJ, Bernard WI. Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response. Int J Cancer 2008; 123: 687-694
    CrossrefPubMedSuche in Google Scholar
  • 10 Adib R, Montgomery JM, Atherton J, OʼRegan L, Richards MW, Straatman KR, Roth D, Straube A, Bayliss R, Moores CA, Fry AM. Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression. Sci Signal 2019; 12: 1-16
    CrossrefPubMedSuche in Google Scholar
  • 11 Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ 2018; 25: 114-132
    CrossrefPubMedSuche in Google Scholar
  • 12 Tadesse S, Anshabo AT, Portman N, Lim E, Tilley W, Caldon CE, Wang S. Targeting CDK2 in cancer: Challenges and opportunities for therapy. Drug Discov Today 2020; 25: 406-413
    CrossrefPubMedSuche in Google Scholar
  • 13 Chen J. The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med 2016; 6: 1-15
    CrossrefPubMedSuche in Google Scholar
  • 14 Aubrey BJ, Kelly GL, Janic A, Herold MJ, Strasser A. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression?. Cell Death Differ 2018; 25: 104-113
    CrossrefPubMedSuche in Google Scholar
  • 15 Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst) 2016; 42: 63-71
    CrossrefPubMedSuche in Google Scholar
  • 16 Al Bitar S, Gali-Muhtasib H. The role of the cyclin dependent kinase inhibitor p21cip1/waf1 in targeting cancer: Molecular mechanisms and novel therapeutics. Cancers (Basel) 2019; 11: 1475
    CrossrefPubMedSuche in Google Scholar
  • 17 Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: A lifeguard with a licence to kill. Nat Rev Mol Cell Biol 2015; 16: 393-405
    CrossrefPubMedSuche in Google Scholar
  • 18 Birkinshaw RW, Czabotar PE. The BCL-2 family of proteins and mitochondrial outer membrane permeabilisation. Semin Cell Dev Biol 2017; 72: 152-162
    CrossrefPubMedSuche in Google Scholar
  • 19 Kim EM, Jung CH, Kim J, Hwang SG, Park JK, Um HD. The p53/p21 complex regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins. Cancer Res 2017; 77: 3092-3100
    CrossrefPubMedSuche in Google Scholar
  • 20 Grilo AL, Mantalaris A. Apoptosis: A mammalian cell bioprocessing perspective. Biotechnol Adv 2019; 37: 459-475
    CrossrefPubMedSuche in Google Scholar
  • 21 Castrogiovanni C, Vandaudenard M, Waterschoot B, De Backer O, Dumont P. Decrease of mitochondrial p53 during late apoptosis is linked to its dephosphorylation on serine 20. Cancer Biol Ther 2015; 16: 1296-1307
    CrossrefPubMedSuche in Google Scholar
  • 22 Eastman A, Kohn EA, Brown MK, Rathman J, Livingstone M, Blank DH, Gribble GW. A novel indolocarbazole, ICP-1, abrogates DNA damage-induced cell cycle arrest and enhances cytotoxicity: similarities and differences to the cell cycle checkpoint abrogator UCN-01. Mol Cancer Ther 2002; 1: 1067-1078
    PubMedSuche in Google Scholar
  • 23 Kohn EA, Ruth ND, Brown MK, Livingstone M, Eastman A. Abrogation of the S phase DNA damage checkpoint results in S phase progression or premature mitosis depending on the concentration of 7-hydroxystaurosporine and the kinetics of Cdc25C activation. J Biol Chem 2002; 277: 26553-26564
    CrossrefPubMedSuche in Google Scholar
  • 24 Bartek J, Lukas J. Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol 2001; 13: 738-747
    CrossrefPubMedSuche in Google Scholar
  • 25 Patil M, Pabla N, Dong Z. Checkpoint kinase 1 in DNA damage response and cell cycle regulation. Cell Mol Life Sci 2013; 70: 4009-4021
    CrossrefPubMedSuche in Google Scholar
  • 26 Zannini L, Delia D, Buscemi G. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol 2014; 6: 442-457
    CrossrefPubMedSuche in Google Scholar
  • 27 Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell 2017; 168: 670-691
    CrossrefPubMedSuche in Google Scholar
  • 28 Welch DR, Hurst DR. Defining the hallmarks of metastasis. Cancer Res 2019; 79: 3011-3027
    CrossrefPubMedSuche in Google Scholar
  • 29 Poltavets V, Kochetkova M, Pitson SM, Samuel MS. The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front Oncol 2018; 8: 431-444
    CrossrefPubMedSuche in Google Scholar
  • 30 Läubli H, Borsig L. Altered cell adhesion and glycosylation promote cancer immune suppression and metastasis. Front Immunol 2019; 10: 2120-2129
    CrossrefPubMedSuche in Google Scholar
  • 31 Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: Beyond the migration of single cells. J Biol Chem 2020; 295: 2495-2505
    CrossrefPubMedSuche in Google Scholar
  • 32 Mezu-Ndubuisi OJ, Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr Res 2021; 89: 1619-1626
    CrossrefPubMedSuche in Google Scholar
  • 33 Haga RB, Ridley AJ. Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases 2016; 7: 207-221
    CrossrefPubMedSuche in Google Scholar
  • 34 Tang DD, Gerlach BD. The roles and regulation of the actin cytoskeleton, intermediate filaments and microtubules in smooth muscle cell migration. Respir Res 2017; 18: 54-66
    CrossrefPubMedSuche in Google Scholar
  • 35 Garcin C, Straube A. Microtubules in cell migration. Essays Biochem 2019; 63: 509-520
    CrossrefPubMedSuche in Google Scholar
  • 36 Munari CC, de Oliveira PF, de Souza Lima IM, de Paula Lima Martins S, de Carvalho da Costa J, Bastos JK, Tavares DC. Evaluation of cytotoxic, genotoxic and antigenotoxic potential of Solanum lycocarpum fruits glicoalkaloid extract in V79 cells. Food Chem Toxicol 2012; 50: 3696-3701
    CrossrefPubMedSuche in Google Scholar
  • 37 Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro . Nat Protoc 2006; 1: 2315-2319
    CrossrefPubMedSuche in Google Scholar
  • 38 Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp 2014; 88: 51046-51054
    PubMedSuche in Google Scholar
  • 39 Chen Y. Cell adhesion assay. Bio Protoc 2012; e98: 1-3
    PubMedSuche in Google Scholar
  • 40 Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2020, San Diego: Dassault Systèmes. 2020
    PubMedSuche in Google Scholar
  • 41 Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol 1995; 245: 43-53
    CrossrefPubMedSuche in Google Scholar
  • 42 Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997; 267: 727-748
    CrossrefPubMedSuche in Google Scholar
  • 43 Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein-ligand docking using GOLD. Proteins 2003; 52: 609-623
    CrossrefPubMedSuche in Google Scholar