Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling
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 t...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/7/6816 |
| _version_ | 1797607707522367488 |
|---|---|
| author | Huideng Long Yue Hou Jun Li Chunhua Song Zheng Ge |
| author_facet | Huideng Long Yue Hou Jun Li Chunhua Song Zheng Ge |
| author_sort | Huideng Long |
| collection | DOAJ |
| description | 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 <i>XPO1</i> and <i>eIF4E</i> was elevated in AML patient cohorts, respectively. <i>XPO1</i> and <i>elF4E</i> 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. |
| first_indexed | 2024-03-11T05:33:25Z |
| format | Article |
| id | doaj.art-17d15e60fe0e42eaa7a8db239bb97c80 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T05:33:25Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-17d15e60fe0e42eaa7a8db239bb97c802023-11-17T16:56:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01247681610.3390/ijms24076816Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC SignalingHuideng Long0Yue Hou1Jun Li2Chunhua Song3Zheng Ge4Department of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, ChinaDepartment of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, ChinaDepartment of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, ChinaHershey Medical Center, Pennsylvania State University Medical College, Hershey, PA 17033, USADepartment of Hematology, Zhongda Hospital, School of Medicine, Southeast University, Institute of Hematology Southeast University, Nanjing 210009, ChinaAcute 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 <i>XPO1</i> and <i>eIF4E</i> was elevated in AML patient cohorts, respectively. <i>XPO1</i> and <i>elF4E</i> 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.https://www.mdpi.com/1422-0067/24/7/6816XPO-1 inhibitorazacitidineacute myeloid leukemiaapoptosiseIF4Ec-MYC |
| spellingShingle | Huideng Long Yue Hou Jun Li Chunhua Song Zheng Ge Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling International Journal of Molecular Sciences XPO-1 inhibitor azacitidine acute myeloid leukemia apoptosis eIF4E c-MYC |
| title | Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling |
| title_full | Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling |
| title_fullStr | Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling |
| title_full_unstemmed | Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling |
| title_short | Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling |
| title_sort | azacitidine is synergistically lethal with xpo1 inhibitor selinexor in acute myeloid leukemia by targeting xpo1 eif4e c myc signaling |
| topic | XPO-1 inhibitor azacitidine acute myeloid leukemia apoptosis eIF4E c-MYC |
| url | https://www.mdpi.com/1422-0067/24/7/6816 |
| work_keys_str_mv | AT huidenglong azacitidineissynergisticallylethalwithxpo1inhibitorselinexorinacutemyeloidleukemiabytargetingxpo1eif4ecmycsignaling AT yuehou azacitidineissynergisticallylethalwithxpo1inhibitorselinexorinacutemyeloidleukemiabytargetingxpo1eif4ecmycsignaling AT junli azacitidineissynergisticallylethalwithxpo1inhibitorselinexorinacutemyeloidleukemiabytargetingxpo1eif4ecmycsignaling AT chunhuasong azacitidineissynergisticallylethalwithxpo1inhibitorselinexorinacutemyeloidleukemiabytargetingxpo1eif4ecmycsignaling AT zhengge azacitidineissynergisticallylethalwithxpo1inhibitorselinexorinacutemyeloidleukemiabytargetingxpo1eif4ecmycsignaling |