Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling

• Published in: International journal of molecular sciences Vol. 24; no. 7; p. 6816
• Main Authors: Long, Huideng, Hou, Yue, Li, Jun, Song, Chunhua, Ge, Zheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2023; MDPI
• Subjects: Acute myeloid leukemia; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; azacitidine; Azacitidine - pharmacology; c-MYC; c-Myc protein; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; China; Cholecystokinin; Comparative analysis; Drug dosages; eIF4E; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; Flow cytometry; Genes; Health aspects; Hematology; Humans; Initiation factor eIF-4E; Karyopherins - metabolism; Leukemia; Leukemia, Myeloid, Acute - metabolism; Malignancy; Mortality; Myc protein; Pathogenesis; Patients; Proteins; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA; Signal Transduction; Synergistic effect; XPO-1 inhibitor; China; apoptosis; XPO-1 inhibitor; eIF4E; acute myeloid leukemia; c-MYC; azacitidine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076816

Acute myeloid leukemia (AML) is a high-mortality malignancy with poor outcomes. Azacitidine induces cell death and demonstrates treatment effectiveness against AML. Selinexor (KPT-330) exhibited significant benefits in combination with typical induction treatment for AML patients. Here, we explore the antitumor effect of KPT-330 combined with AZA in AML through CCK-8, flow cytometry, RT-qPCR, western blot, and RNA-seq. Our results showed that KPT-330 combined with AZA synergistically reduced cell proliferation and induced apoptosis in AML primary cells and cell lines. Compared to the control, the KPT-330 plus AZA down-regulates the expression of XPO1, eIF4E, and c-MYC in AML. Moreover, the knockdown of c-MYC could sensitize the synergy of the combination on suppression of cell proliferation and promotion of apoptosis in AML. Moreover, the expression of and was elevated in AML patient cohorts, respectively. and overexpression was associated with poor prognosis. In summary, KPT-330 with AZA exerted synergistic effects by suppressing XPO1/eIF4E/c-MYC signaling, which provided preclinical evidence for further clinical application of the novel combination in AML.