Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells

Autor(es)

Mateus Reis-Silva, Catarina Sofia ^[1] ; Branco, Paola Cristina ^[1] ; Lima, Keli ^{[1, 2]} ; Silva, Fabiana Lima ^[3] ; Hrihorowitsch Moreno, Paulo Roberto ^[3] ; Guallar, Victor ^{[4, 5]} ; Costa-Lotufo, Leticia Veras ^[1] ; Machado-Neto, Joao Agostinho ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Med, Dept Hematol, Lab Med Invest Pathogenesis & Targeted Therapy On, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Chem, Sao Paulo - Brazil

^[4] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona - Spain

^[5] Barcelona Supercomp Ctr BSC, Barcelona - Spain

• Tipo de documento: Artigo Científico
• Fonte: TOXICOLOGY IN VITRO; v. 76, OCT 2021.
• Citações Web of Science: 0

Resumo

Acute myeloid leukemia (AML) belongs to a group of hematological cancer whose relapse cases are often associated with chemoresistance that impairs treatment success and contributes to a poor outcome. For this reason, there is an urgent need for the development of new therapeutic strategies. Herein, we explore the combination of venetoclax, a BCL2 inhibitor, and embelin, an XIAP inhibitor, in the AML cell lines. Combinatory treatment of venetoclax and embelin potentiated cytotoxic effects of these drugs, demonstrating that both in combination present lower IC50 values than single treatment of either venetoclax or embelin alone in both cell lines analyzed. The combinatory treatment further increased the apoptosis-inducing properties of both compounds. Computer simulations suggest that embelin binds to both BIR2 and BIR3 domains of XIAP, reinforcing this inhibitory apoptosis protein as an embelin target. Although all AML cell lines presented similar basal levels of XIAP, the combinatory treatment effectively inhibited XIAP expression in OCI-AML3 cells. In conclusion, the inhibition of both apoptosis inhibitory players, BCL2 and XIAP, by venetoclax and embelin, respectively, potentiated their cytotoxic effects in AML cell lines. (AU)

• Processo FAPESP: 17/09022-8 - Proteínas Inibidoras da Apoptose (IAPs) como alvo terapêutico no melanoma: estudos com prodigininas em células resistentes ao vemurafenibe
• Beneficiário: Paola Cristina Branco
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
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• Modalidade de apoio: Auxílio à Pesquisa - Regular
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• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
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• Modalidade de apoio: Bolsas no Brasil - Mestrado