Bioscreening of polyphenols with anticancer activity and investigation of the molecular mechanisms involving the p53 transcription factor

• Grant number: 17/03237-2
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2017
• End date: May 31, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Mozart de Azevedo Marins
• Grantee: Mozart de Azevedo Marins
• Host Institution: Universidade de Ribeirão Preto (UNAERP). Campus Ribeirão Preto. Ribeirão Preto , SP, Brazil
• Associated researchers: Ana Lucia Fachin Saltoratto ; Luis Octávio Regasini ; Valdir Cechinel Filho
• Associated research grant(s): 18/50008-1 - Synthesis and discovery of molecular mechanisms of some novel conjugated unsaturated ketones designed as anticancer agents, AP.R SPRINT
• Associated scholarship(s): 18/19648-4 - Transduction with shRNA library and generation of mutant strains in U2OS cells, BP.TT; 18/18067-8 - Screening of polyphenols with cytotoxic activity and inhibition of cell migration / invasion, BP.TT

Abstract

p53 protein is a transcription factor with tumor suppressor activity that plays a key role in the development of cancer. In most known cancers, p53 has its activity compromised by mutations in its protein sequence or by the deregulation of mechanisms that control its cellular levels, such as overexpression of the MDM2 protein, the major p53-negative regulator. Mutations in p53 may also give rise to mutant p53 proteins that have oncogenic activity. Therefore, identifying ways to recover normal p53 activity is an interesting strategy to be applied in the development of cancer treatment therapies. In our previous project, we identified chalcones, a polyphenol present in plants and with anticancer activity, that can stabilize wild p53 and activate the expression of several genes under its control. This stabilization involves the interaction of p53 to proteins such as MDM2, Hsp40 and ATF3. In this project, we propose experiments to identify new polyphenols with the ability to stabilize wild p53 or reverse the oncogenic activity of mutant forms via interaction with Hsp40 and ATF3 in tumor cell lines. With quantitative RT-PCR, western blot, gene silencing and protein immunoprecipitation we also propose the study of the effect of molecules identified in the processes of apoptosis and epithelial to mesenchymal transition, important factors for cancer. Our final goal is the identification of molecules to use in preclinical validation studies with animal models where we search for molecules that can reverse the development of tumors through stabilization or recovery of p53 activity. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SILVA, GABRIEL; LIMA, FELIPE TEIXEIRA; SEBA, VIVIANE; MENDES LOURENCO, ANA LAURA; LUCAS, THAISE GRAMINHA; DE ANDRADE, BIANCA VIEIRA; TORREZAN, GUILHERME SILVA; POLAQUINI, CARLOS ROBERTO; GARCIA, MARCELO ENGRACIA; COUTO, LUCELIO BERNARDES; et al. Curcumin Analog CH-5 Suppresses the Proliferation, Migration, and Invasion of the Human Gastric Cancer Cell Line HGC-27. Molecules, v. 23, n. 2, FEB 2018. (17/03237-2, 14/18330-0, 14/15307-7)

LIMA, FELIPE TEIXEIRA; SEBA, VIVIANE; SILVA, GABRIEL; TORREZAN, GUILHERME SILVA; POLAQUINI, CARLOS ROBERTO; PINHANELLI, VITOR CARESSATO; BAEK, SEUNG J.; FACHIN, ANA LUCIA; REGASINI, LUIS OCTAVIO; MARINS, MOZART. The Curcumin Analog CH-5 Exerts Anticancer Effects in Human Osteosarcoma Cells via Modulation of Transcription Factors p53/Sp1. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 7, JUL 2018. (17/03237-2, 14/15307-7, 14/18330-0)

SEBA, VIVIANE; SILVA, GABRIEL; DOS SANTOS, MARIANA BASTOS; BAEK, SEUNG JOON; FRANCA, SUZELEI DE CASTRO; FACHIN, ANA LUCIA; REGASINI, LUIS OCTAVIO; MARINS, MOZART. Chalcone Derivatives 4 `-Amino-1-Naphthyl-Chalcone (D14) and 4 `-Amino-4-Methyl-1-Naphthyl-Chalcone (D15) Suppress Migration and Invasion of Osteosarcoma Cells Mediated by p53 Regulating EMT-Related Genes. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 9, SEP 2018. (17/03237-2, 14/15307-7)

SEBA, VIVIANE; DE LIMA, GABRIEL GOETTEN; PEREIRA, BRUNO L.; SILVA, GABRIEL; REINHARDT, LUIZA STEFFENS; ARANTES, PABLO RICARDO; CHEE, BOR SHIN; DOS SANTOS, MARIANA BASTOS; FRANCA, SUZELEI C.; REGASINI, LUIS OCTAVIO; et al. Development, Characterization and Cell Viability Inhibition of PVA Spheres Loaded with Doxorubicin and 4 `-Amino-1-Naphthyl-Chalcone (D14) for Osteosarcoma. POLYMERS, v. 13, n. 16, AUG 2021. (17/03237-2, 19/03074-1)

SEBA, VIVIANE; SILVA, GABRIEL; DOS SANTOS, MARIANA BASTOS; BAEK, SEUNG JOON; FRANCA, SUZELEI DE CASTRO; FACHIN, ANA LUCIA; REGASINI, LUIS OCTAVIO; MARINS, MOZART. Chalcone Derivatives 4 '-Amino-1-Naphthyl-Chalcone (D14) and 4 '-Amino-4-Methyl-1-Naphthyl-Chalcone (D15) Suppress Migration and Invasion of Osteosarcoma Cells Mediated by p53 Regulating EMT-Related Genes. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 9, p. 13-pg., 2018-09-01. (14/15307-7, 17/03237-2)

LIMA, FELIPE TEIXEIRA; SEBA, VIVIANE; SILVA, GABRIEL; TORREZAN, GUILHERME SILVA; POLAQUINI, CARLOS ROBERTO; PINHANELLI, VITOR CARESSATO; BAEK, SEUNG J.; FACHIN, ANA LUCIA; REGASINI, LUIS OCTAVIO; MARINS, MOZART. The Curcumin Analog CH-5 Exerts Anticancer Effects in Human Osteosarcoma Cells via Modulation of Transcription Factors p53/Sp1. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, n. 7, p. 14-pg., 2018-07-01. (14/15307-7, 17/03237-2, 14/18330-0)