Rational design and development of new prototypes derived of antitumor phospholipids as potential inhibitors of the enzyme CtP: phosphoethanolamine citidililtransferase and antitumor agents in non-small cell lung cancer

• Grant number: 13/07273-2
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2013 - October 31, 2015
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Jose Alexandre Marzagão Barbuto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Cristoforo Scavone ; Kerly Fernanda Mesquita Pasqualoto ; Liliana Marzorati ; Marcio Henrique Zaim

Abstract

Due to the relative lack of success of the existent treatments against lung cancers, it is of utmost urgency to develop new, efficient and selective therapies against this disease that is responsible for millions of deaths worldwide. In this regard, the purpose of this proposal is the development of a novel class of drugs candidates, which might offer the possibility of a disease free life to patients. As opposed to the majority of currently chemotherapeutic drugs, antineoplastic phospholipids (AFTs) do not have DNA as a target, but modify the cell membrane turnover, ultimately inducing death by apoptosis, with a high selectivity for tumor cells. The main hypothesis is that the AFT's antitumor effects are due to the inhibition of CTP:phosphocholine cytidylyltransferase enzyme in the phospholipid biosynthetic pathway, known as the Kennedy pathway, which blocks the synthesis of phosphatidylcholine and causes the accumulation of ceramide, commonly associated with apoptosis. Likewise, the inhibition of phosphatidylethanolamine synthesis stops the cell division by preventing the correct progression of cytokinesis, and also induces a topological impairment of the trans-membrane protein domains, mainly those in mitochondria. This, in turn, affects the cellular bioenergetics, eventually triggering death by apoptosis, and impairs lipids signaling, which is directly associated with the regulation of mitogen-activated protein kinase (MAPKs) mediated signaling pathways. Therefore, the inhibition of the phosphatidylethanolamine synthesis constitutes a promising strategy for the identification of novel antitumor compounds, and the CTP:phosphoethanolamine cytidylyltransferase, which is a key enzyme in the Kennedy pathway and uses phophoethanolamine as a substrate, becomes the main potential target, with innovative character, for the development of antitumor drugs. This project aims to establish an interactive and multidisciplinary cycle regarding the development and optimization of novel leads (new chemical entities), acting as CTP:phosphoethanolamine cytidylyltransferase inhibitors as well as antitumor potential agents, integrating the computer-aided drug design (CADD), organic chemistry and experimental evaluation research fields. (AU)

Scientific publications

(9)

(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)

TEIXEIRA, SARAH FERNANDES; DE AZEVEDO, RICARDO ALEXANDRE; SILVA, ARTHUR CARVALHO; BRAGA, RODOLPHO CAMPOS; JORGE, SALOMAO DORIA; MARZAGAO BARBUTO, JOSE ALEXANDRE; ANDRADE, CAROLINA HORTA; FERREIRA, ADILSON KLEBER. Evaluation of cytotoxic effect of the combination of a pyridinyl carboxamide derivative and oxaliplatin on NCI-H1299 human non-small cell lung carcinoma cells. BIOMEDICINE & PHARMACOTHERAPY, v. 84, p. 1019-1028, DEC 2016. (14/07341-0, 14/24455-0, 16/05351-4, 13/07273-2, 15/18528-7, 09/54599-5, 13/05396-0, 14/14267-1)

MAMBELLI, LISLEY I.; TEIXEIRA, SARAH F.; JORGE, SALOMAO D.; KAWAMURA, BARBARA; MENEGUELO, RENATO; BARBUTO, JOSE A. M.; DE AZEVEDO, RICARDO A.; FERREIRA, ADILSON K.. Phosphoethanolamine induces caspase-independent cell death by reducing the expression of C-RAF and inhibits tumor growth in human melanoma model. BIOMEDICINE & PHARMACOTHERAPY, v. 103, p. 18-28, JUL 2018. (13/07273-2, 16/07519-0, 17/01265-9, 15/18528-7, 14/14267-1, 16/09392-7)

DE SA JUNIOR, PAULO LUIZ; DIAS CAMARA, DIANA APARECIDA; PORCACCHIA, ALLAN SAJ; MOREIRA FONSECA, PAMELA MARIA; JORGE, SALOMAO DORIA; ARALDI, RODRIGO PINHEIRO; FERREIRA, ADILSON KLEBER. The Roles of ROS in Cancer Heterogeneity and Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2017. (13/07273-2, 15/18528-7)

FERREIRA, ADILSON KLEBER; MESQUITA PASQUALOTO, KERLY FERNANDA; KRUYT, FRANK A. E.; PALACE-BERL, FANNY; AZEVEDO, RICARDO ALEXANDRE; TURRA, KELY MEDEIROS; RODRIGUES, CECILIA PESSOA; FRANCO FERREIRA, ANA CAROLINA; CLAVIJO SALOMON, MARIA ALEJANDRA; DE SA JUNIOR, PAULO LUIZ; et al. BFD-22 a new potential inhibitor of BRAF inhibits the metastasis of B16F10 melanoma cells and simultaneously increased the tumor immunogenicity. Toxicology and Applied Pharmacology, v. 295, p. 56-67, MAR 15 2016. (14/07341-0, 13/07273-2, 09/54599-5, 13/05396-0, 14/14267-1)

TAMAYO, LENKA V.; GOUVEA, LIGIANE R.; SOUSA, ANNA C.; ALBUQUERQUE, RONNIEL M.; TEIXEIRA, SARAH FERNANDES; DE AZEVEDO, RICARDO ALEXANDRE; LOURO, SONIA R. W.; FERREIRA, ADILSON KLEBER; BERALDO, HELOISA. Copper(II) complexes with naringenin and hesperetin: cytotoxic activity against A 549 human lung adenocarcinoma cells and investigation on the mode of action. BIOMETALS, v. 29, n. 1, p. 39-52, FEB 2016. (09/54599-5, 13/07273-2)

FERREIRA, ADILSON KLEBER; TAVARES, MAURICIO TEMOTHEO; MESQUITA PASQUALOTO, KERLY FERNANDA; DE AZEVEDO, RICARDO ALEXANDRE; TEIXEIRA, SARAH FERNANDES; FERREIRA-JUNIOR, WILSON ALVES; BERTIN, ARIANE MATIELLO; DE-SA-JUNIOR, PAULO LUIZ; MARZAGO BARBUTO, JOSE ALEXANDRE; FIGUEIREDO, CARLOS ROGERIO; et al. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model. TUMOR BIOLOGY, v. 36, n. 9, p. 7251-7267, SEP 2015. (13/07273-2, 13/18160-4, 12/23233-8)

FERREIRA, ADILSON K.; MAMBELLI, LISLEY I.; PILLAI, SARAVANAN Y.. Intervening in disease through genetically-modified bacteria. BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY, v. 31, n. 6, p. 693-697, DEC 2017. (13/07273-2, 15/18528-7)

TEIXEIRA, SARAH F.; RODRIGUES, CECILIA P.; COSTA, CICERO J. S.; PETTINATI, THAIS N.; DE AZEVEDO, RICARDO A.; MAMBELLI, I, LISLEY; JORGE, SALOMAO D.; RAMOS, RODRIGO N.; FERRO, EMER S.; BARBUTO, JOSE A. M.; et al. Edelfosine: An Antitumor Drug Prototype. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 18, n. 6, p. 865-874, 2018. (14/24455-0, 13/07273-2, 16/07519-0, 15/18528-7, 16/09392-7)

TEIXEIRA, SARAH FERNANDES; DE AZEVEDO, RICARDO ALEXANDRE; CLAVIJO SALOMON, MARIA ALEJANDRA; JORGE, SALOMAO DORIA; LEVY, DEBORA; BYDLOWSKI, SERGIO PAULO; RODRIGUES, CECILIA PESSOA; PIZZO, CELIA REGINA; MARZAGAO BARBUTO, JOSE ALEXANDRE; FERREIRA, ADILSON KLEBER. Synergistic anti-tumor effects of the combination of a benzofuroxan derivate and sorafenib on NCI-H460 human large cell lung carcinoma cells. BIOMEDICINE & PHARMACOTHERAPY, v. 68, n. 8, p. 1015-1022, OCT 2014. (09/54599-5, 13/07273-2)