Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models.
Nat Med
; 24(2): 194-202, 2018 02.
Article
em En
| MEDLINE
| ID: mdl-29334372
ABSTRACT
The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema ASC de Transporte de Aminoácidos
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Bibliotecas de Moléculas Pequenas
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Glutamina
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Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Revista:
Nat Med
Ano de publicação:
2018
Tipo de documento:
Article