Embelin potentiates venetoclax-induced apoptosis in acute myeloid leukemia cells

• Published in: Toxicology in vitro 2021-10, Vol.76, p.105207-105207, Article 105207
• Main Authors: Reis-Silva, Catarina Sofia Mateus, Branco, Paola Cristina, Lima, Keli, Silva, Fabiana Lima, Moreno, Paulo Roberto Hrihorowitsch, Guallar, Victor, Costa-Lotufo, Leticia Veras, Machado-Neto, João Agostinho
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzoquinones - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; DNA Damage; Drug Synergism; Embelin; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Sulfonamides - pharmacology; Venetoclax; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - metabolism
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2021.105207

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. [Display omitted] •Venetoclax-based therapy displays interesting results in poor prognosis AML patients.•Venetoclax activates intrinsic apoptosis targeting BCL2 protein.•Embelin is a natural product that potentially inhibits XIAP, a caspase inhibitor.•Embelin potentiates venetoclax-induced apoptosis in AML cellular models.•IAP-targeting drugs as a putative anticancer option for overcome AML resistance.