Guttiferone E Displays Antineoplastic Activity Against Melanoma Cells

Arthur Barcelos Ribeiro; Heloiza Diniz Nicolella; Lucas Henrique Domingos da Silva; Jennyfer Andrea Aldana Mejía; Matheus Hikaru Tanimoto; Sérgio Ricardo Ambrósio; Jairo Kenupp Bastos; Renato Pereira Orenha; Renato Luis Tame Parreira; Denise Crispim Tavares

doi:10.1055/a-1890-5446

Planta Medica, Inhaltsverzeichnis

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

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

,

Heloiza Diniz Nicolella

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

,

Lucas Henrique Domingos da Silva

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

,

Jennyfer Andrea Aldana Mejía

²School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

,

Matheus Hikaru Tanimoto

²School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

,

Sérgio Ricardo Ambrósio

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

,

Jairo Kenupp Bastos

²School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

,

Renato Pereira Orenha

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

,

Renato Luis Tame Parreira

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

,

Denise Crispim Tavares

¹University of Franca, Avenida Dr. Armando Salles Oliveira, Franca, São Paulo, Brazil

› Institutsangaben

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

Volltext

Referenzen

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
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
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
4 Wu SB, Long C, Kennelly EJ. Structural diversity and bioactivities of natural benzophenones. Nat Prod Rep 2014; 31: 1158-1174
5 Surana K, Chaudhary B, Diwaker M, Sharma S. Benzophenone: A ubiquitous scaffold in medicinal chemistry. Medchemcomm 2018; 9: 1803-1817
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
7 López BG, Schmidt EM, Eberlin MN, Sawaya AC. Phytochemical markers of different types of red propolis. Food Chem 2014; 146: 174-180
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
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
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
11 Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ 2018; 25: 114-132
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
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
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
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
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
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
18 Birkinshaw RW, Czabotar PE. The BCL-2 family of proteins and mitochondrial outer membrane permeabilisation. Semin Cell Dev Biol 2017; 72: 152-162
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
20 Grilo AL, Mantalaris A. Apoptosis: A mammalian cell bioprocessing perspective. Biotechnol Adv 2019; 37: 459-475
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
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
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
24 Bartek J, Lukas J. Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol 2001; 13: 738-747
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
26 Zannini L, Delia D, Buscemi G. CHK2 kinase in the DNA damage response and beyond. J Mol Cell Biol 2014; 6: 442-457
27 Lambert AW, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell 2017; 168: 670-691
28 Welch DR, Hurst DR. Defining the hallmarks of metastasis. Cancer Res 2019; 79: 3011-3027
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
30 Läubli H, Borsig L. Altered cell adhesion and glycosylation promote cancer immune suppression and metastasis. Front Immunol 2019; 10: 2120-2129
31 Janiszewska M, Primi MC, Izard T. Cell adhesion in cancer: Beyond the migration of single cells. J Biol Chem 2020; 295: 2495-2505
32 Mezu-Ndubuisi OJ, Maheshwari A. The role of integrins in inflammation and angiogenesis. Pediatr Res 2021; 89: 1619-1626
33 Haga RB, Ridley AJ. Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases 2016; 7: 207-221
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
35 Garcin C, Straube A. Microtubules in cell migration. Essays Biochem 2019; 63: 509-520
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
37 Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro . Nat Protoc 2006; 1: 2315-2319
38 Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp 2014; 88: 51046-51054
39 Chen Y. Cell adhesion assay. Bio Protoc 2012; e98: 1-3
40 Dassault Systèmes BIOVIA, Discovery Studio Modeling Environment, Release 2020, San Diego: Dassault Systèmes. 2020
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
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
43 Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein-ligand docking using GOLD. Proteins 2003; 52: 609-623

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