Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: TOXICOLOGY IN VITRO; v. 76, OCT 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 17/09022-8 - Inhibitory Apoptosis Proteins (IAPs) as therapeutic targets in melanoma: studies with prodiginines in vemurafenibe-resistant cells
• Grantee: Paola Cristina Branco
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Leticia Veras Costa Lotufo
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 18/06522-2 - Use of bioaffinity chromatography in the prospecting of anticancer substances in marine actinomycetes: XIAP and STMN1 as pharmacological targets
• Grantee: Catarina Sofia Mateus Reis e Silva
• Support Opportunities: Scholarships in Brazil - Master