An oral triple pill-based cocktail effectively controls acute myeloid leukemia with high translation

• Published in: Biomedicine & pharmacotherapy Vol. 167; p. 115584
• Main Authors: Li, Mengyuan, Zheng, Shuwen, Gong, Qinyuan, Zhuang, Haifeng, Wu, Zhaoxing, Wang, Ping, Zhang, Xuzhao, Xu, Rongzhen
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 01.11.2023; Elsevier
• Subjects: Acute myeloid leukemia; Bcl-2i; Cocktail therapy; HHT; P-gpi; AML; Navi; TAR; DMSO; PDX; HAD; HAACT; MTT; TPM; AACR; CHX; HHT; HA; HSCs; ENC; MTD; LSC; Acute myeloid leukemia; Bcl-2i; VEN; HPLC; P-gpi; Cocktail therapy
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.115584

Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy. [Display omitted] •P-gp is one of the critical causes of the low efficacy of single-agent HHT in AML.•P-gp inhibitor ENC enhances HHT anti-cancer efficacy both in vitro and in vivo.•The oral triple pill-based cocktail of HHT/ENC/VEN exhibits satisfactory anti-tumor efficacy.•Cocktail reverses oncogenic translation addiction in AML.•EphB4/Bcl-xL could be a potential molecular biomarker of Cocktail response.