New applications of phenothiazines and Palladacycles: nanostructured systems to the mechanistic study of death in tumor cells

• Grant number: 12/12247-8
• Support Opportunities: Regular Research Grants
• Duration: October 01, 2012 - September 30, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Tiago Rodrigues
• Grantee: Tiago Rodrigues
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Associated researchers: Daniele Ribeiro de Araujo ; Edgar Julian Paredes-Gamero ; Giselle Zenker Justo ; Ivarne Luis dos Santos Tersariol

Abstract

According to the estimative of national and international organizations, cancer incidence has grown alarmingly in world population due to the elevation of life expectancy and some habits adopted by population that constitutes risk factors for the development of this disease. Therefore, beyond earlier diagnosis and prevention, it is noteworthy the development of safe and efficacy therapies to cancer treatment. This highlights the need for a better comprehension of the cell death biochemical pathways developed by the tumor cells, since the major problems encountered in antitumor chemotherapy are still drug resistance and the lack of knowledge of morphological and functional alterations displayed by tumor cells to evade cell death pathways. Data previously published from our lab demonstrated that phenothiazines present a potent antioxidant activity that inhibits mitochondrial permeability transition (MPT) at low concentrations (RODRIGUES et al., 2002). However, at high concentrations they are able to oxidize mitochondrial membrane thiol groups and, in the presence of calcium, induce MPT and cytochrome c release, events associated with the induction of apoptosis (CRUZ et al., 2010). Furthermore, when photoexcited, phenotiazines generate cation radicals (RODRIGUES et al., 2006) able to cause lipoperoxidation in isolated mitochondria (RODRIGUES et al., 2005). We have also demonstrated that another class of compounds, the palladacycles, is able to oxidize protein thiol groups and promote mitochondrial permeabilization associated to cell death (SANTANA et al., 2009). Thus, in this project we intend to continue these studies and investigate the phenotiazines- and palladacycles-induced cell death in tumor cells, analyzing in details the molecular mechanisms of cell death and alterations in the gene expression induced by these drugs. Also, the effect of nanoparticulate systems containing these drugs in cell death will also be studied. It is expected with these systems an increase in antitumor efficacy allowing a reduction of the drug dosage necessary to kill tumor cells, avoiding possible collateral effects in case of clinical use. (AU)

Scientific publications

(8)

(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)

MEDEIROS, HYLLANA C. D.; COLTURATO-KIDO, CARINA; FERRAZ, LETICIA S.; COSTA, CLAUDIA A.; MORAES, VIVIAN W. R.; PAREDES-GAMERO, EDGAR JULIAN; TERSARIOL, IVARNE L. S.; RODRIGUES, TIAGO. AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia. Chemico-Biological Interactions, v. 315, JAN 5 2020. (16/07367-5, 12/12247-8)

DE FIGUEIREDO, LAYSA P.; IBIAPINO, AMANDA L.; DO AMARAL, DANIEL N.; FERRAZ, LETICIA S.; RODRIGUES, TIAGO; BARREIRO, ELIEZER J.; LIMA, LIDIA M.; FERREIRA, FABIO F.. Structural characterization and cytotoxicity studies of different forms of a combretastatin A4 analogue. Journal of Molecular Structure, v. 1147, p. 226-234, NOV 5 2017. (12/12247-8)

FERRAZ, LETICIA S.; WATASHI, CAROLINA M.; COLTURATO-KIDO, CARINA; PELEGRINO, MILENA T.; PAREDES-GAMERO, EDGAR J.; WELLER, RICHARD B.; SEABRA, AMEDEA B.; RODRIGUES, TIAGO. Antitumor Potential of S-Nitrosothiol-Containing Polymeric Nanoparticles against Melanoma. MOLECULAR PHARMACEUTICS, v. 15, n. 3, SI, p. 1160-1168, MAR 2018. (12/12247-8, 16/07367-5)

MORAES, V. W. R.; CAIRES, A. C. F.; PAREDES-GAMERO, E. J.; RODRIGUES, T.. Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells. CELL DEATH & DISEASE, v. 4, JUN 2013. (12/12247-8)

DE MELLO, JOYCE C.; MORAES, VIVIAN W. R.; WATASHI, CAROLINA M.; DA SILVA, DEYSE C.; CAVALCANTI, LEIDE P.; FRANCO, MARGARETH K. K. D.; YOKAICHIYA, FABIANO; DE ARAUJO, DANIELE R.; RODRIGUES, TIAGO. Enhancement of chlorpromazine antitumor activity by Pluronics F127/L81 nanostructured system against human multidrug resistant leukemia. PHARMACOLOGICAL RESEARCH, v. 111, p. 102-112, SEP 2016. (13/05099-5, 12/12247-8, 11/21433-7)

PHILOT, ERIC ALLISON; LOPES, DAVID DA MATA; DE SOUZA, ARYANE TOFANELLO; KIMUS BRAZ, ANTONIO SERGIO; NANTES, ISELI LOURENCO; RODRIGUES, TIAGO; PERAHIA, DAVID; MITEVA, MARIA A.; BARBOUR SCOTT, LUIS PAULO. Binding of phenothiazines into allosteric hydrophobic pocket of human thioredoxin 1. EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, v. 45, n. 3, p. 279-286, APR 2016. (12/07456-7, 11/11857-4, 12/12247-8)

JABES, DANIELA LEITE; DE FREITAS OLIVEIRA, ANA CLAUDIA; ALENCAR, VALQUIRIA CAMPOS; MENEGIDIO, FABIANO BEZERRA; SOUZA RENO, DEBORA LILIANE; SANTOS, DAIENE SOUZA; BARBOSA, DAVID ACIOLE; VILAS BOAS, RENATA OZELAMI; DE OLIVEIRA RODRIGUES CUNHA, RODRIGO LUIZ; RODRIGUES, TIAGO; et al. Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis. Molecular Genetics and Genomics, v. 291, n. 3, p. 1347-1362, JUN 2016. (12/12247-8)

DE FARIA, PRISCILA A.; BETTANIN, FERNANDA; CUNHA, RODRIGO L. O. R.; PAREDES-GAMERO, EDGAR J.; HOMEM-DE-MELLO, PAULA; NANTES, ISELI L.; RODRIGUES, TIAGO. Cytotoxicity of phenothiazine derivatives associated with mitochondrial dysfunction: A structure-activity investigation. Toxicology, v. 330, p. 44-54, APR 1 2015. (12/12247-8, 10/19790-3)

Filed patent(s) as a result of this research project