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Validation of CTP:phosphoethanolamine cytidylyltransferase enzyme and ethanolamine transport as new targets for the rational development of new drugs in non-small cell lung cancer treatment

Grant number: 16/09392-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2016
Effective date (End): October 31, 2019
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Emer Suavinho Ferro
Grantee:Sarah Fernandes Teixeira
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:15/18528-7 - Development of new drug candidate for the treatment of non-small cell lung cancer: CHY-1 as a novel inhibitor of autophagy and prototype of a novel class of inhibitors of the enzyme CTP: phosphoethanolamine citidililtransferase, AP.JP

Abstract

Lung cancer is a challenge to public health because of its high incidence and mortality in the world. Thus, it is urgent to search for new therapies for its treatment. The intervention of the metabolism of phospholipids, specially for phosphatidylethanolamine (PE), has an important potential for the development of new treatment strategies for lung cancer. The PE is a major component of cell membranes and is related to tumor progression. It should also be noted that the EP is increased in tumor tissue samples from patients with lung cancer of non-small cell lung cancer (NSCLC). The main route of PE synthesis is Kennedy pathway, whose limiting step is performed by the enzyme CTP: citidilil-phosphoethanolamine transferase (Pcyt2), often overexpressed in neoplastic cells including lung cancer cells. There are also other minor routes for PE production, but these other routes depend on the input from its initial substrate, ethanolamine. Thus, its availability restricts the production of PE. In this context the availability of ethanolamine is determined primarily by transport to cytosol, via a transporter and vesicles distribution. Thus, given the importance of PE in tumor development and the mechanisms involved in its production, there are two potential targets that can be addressed in the metabolism of PE: the Pcyt2 enzyme and the transport of ethanolamine. In the present project we intend to evaluate in vitro and in vivo the ability of modulating the expression and activity of Pcyt2 enzyme and the inhibition of ethanolamine transport in models of NSCLC. We aim to validate the therapeutic potential of these targets for rational development of new drugs for the treatment of NSCLC.

Scientific publications
(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)
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. Web of Science Citations: 1.
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.; FERREIRA, ADILSON K. Edelfosine: An Antitumor Drug Prototype. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 18, n. 6, p. 865-874, 2018. Web of Science Citations: 0.

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