Overcoming venetoclax resistance through heme-mediated NOXA/cyclin D1/Mcl-1 axis with a novel artemisinin conjugate.

ABSTRACT:

Abstract

The B-cell lymphoma protein 2 (Bcl-2) inhibitor venetoclax remains the sole apoptosis-inducing agent approved for combination therapy in older patients with acute myeloid leukemia (AML). However, its clinical efficacy is frequently constrained by the emergence of drug resistance, which involves the overexpression or induction of the myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xL) proteins. To address this challenge, we developed a novel strategy to enhance venetoclax activity and overcome resistance by producing NOXA through the conjugation of dihydroartemisinin (DHA) to venetoclax using a chemical synthesis approach. The produced conjugate, A1, retained potent Bcl-2 inhibitory activity and significantly enhanced NOXA production by promoting intera

SUBMITTER: Zhang J 

PROVIDER: S-EPMC12607026 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature