Edelfosine: An Antitumor Drug Prototype

Autor(es):Mostrar menos -

Teixeira, Sarah F. ^{[1, 2]} ; Rodrigues, Cecilia P. ^[2] ; Costa, Cicero J. S. ^[2] ; Pettinati, Thais N. ^[2] ; de Azevedo, Ricardo A. ^[3] ; Mambelli, I, Lisley ; Jorge, Salomao D. ^{[3, 4]} ; Ramos, Rodrigo N. ^[4] ; Ferro, Emer S. ^[1] ; Barbuto, Jose A. M. ^[4] ; Ferreira, Adilson K. ^{[5, 3, 4]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, CIETEC IPEN, Dept Oncol, Alchemy Innovat Res & Dev, Sao Paulo - Brazil

^[4] Mambelli, Lisley, I, Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Med Sch, Med Sci, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY; v. 18, n. 6, p. 865-874, 2018.
• Citações Web of Science: 0

Resumo

Background: Lung cancer is the most prevalent cancer and a high fatality disease. Despite of all available therapeutic approaches, drug resistance of chemotherapy agents for patients remain as an obstacle. New drugs integrating immunotherapeutic and conventional cytotoxic effects is a powerful strategy for the treatment of cancer to overcome this limitation. Antineoplastic phospholipids combine both of these activities by affecting lipid metabolism and signaling through lipid rafts. Therefore, they emerge as interesting scaffolds for designing new drugs. Objective: We aimed to evaluate antineoplastic phospholipids as scaffolds for designing new drugs for lung cancer treatment. Methods: The initial screening in A549 cells was performed by MTT assay. Others cytotoxic effects were evaluated in A549 cells by clonogenic assay, Matrigel 3D culture and flow cytometry analyses of cell cycle, apoptosis, mitochondrial membrane electronic potential and superoxide production. Immunological effects of ED were accessed on dendritic cells (DCs) and the expression of some markers were evaluated by flow cytometry. In vivo lung colonization analysis was performed after intravenously injection of A549 cells and daily treatment with ED. Results: Herein, ED showed to be the most efficient compound concerning cytotoxic, thereby, ED was selected for following tests. ED showed a cytotoxic profile in both monolayer and 3D culture and also in vivo models using A549 cells. This profile is due to G0/G1 phase cellular arrest and apoptosis drove by mitochondrial membrane depolarization and superoxide overproduction. Moreover, ED modulated DCs toward an activated pattern by the increased expression of CD83 and a remarkable decreased expression of PD-L1/CD274 on DCs membrane. Conclusions: Thus, ED is an interesting antitumor drug prototype due to not only its direct cellular cytotoxicity but also given its immunological features. (AU)

• Processo FAPESP: 16/09392-7 - Validação da enzima ctp:fosfoetanolamina-citidilil-transferase e do transporte de etanolamina como novos alvos para o desenvolvimento racional de novos fármacos para o tratamento do carcinoma de pulmão de não-pequenas células
• Beneficiário: Sarah Fernandes Teixeira
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/07519-0 - Desenvolvimento do CHY-1 como um novo candidato a fármaco para o tratamento de diferentes subtipos de câncer de mama
• Beneficiário: Lisley Inata Mambelli
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/07273-2 - Planejamento racional e desenvolvimento de novos protótipos derivados de fosfolipídios antitumorais como inibidores potenciais da enzima CTP: fosfoetanolamina citidililtransferase e agentes antitumorais em carcinoma de pulmão de não pequenas células
• Beneficiário: Jose Alexandre Marzagão Barbuto
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/18528-7 - Desenvolvimento de novo candidato a fármaco para o tratamento do carcinoma de pulmão de células não pequenas: CHY-1, inibidor de autofagia e protótipo de nova classe de inibidores da enzima CTP: fosfoetanolamina citidililtransferase
• Beneficiário: Adilson Kleber Ferreira
• Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
• Processo FAPESP: 14/24455-0 - Avaliação da atividade do CHY-1, um novo análogo da miltefosina, como potencial inibidor da enzima CTP: fosfoetanolamina citidililtransferase, sobre o carcinoma de pulmão de não-pequenas células
• Beneficiário: Sarah Fernandes Teixeira
• Linha de fomento: Bolsas no Brasil - Mestrado