Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways
Abstract Dysregulation of MDM2, a p53 negative regulator, frequently occurs in acute myeloid leukemia (AML) and is associated with unfavorable prognoses, rendering the p53-MDM2 axis an attractive target for the development of small-molecule inhibitors. MDM2 antagonists have been intensely developed...
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40164-022-00276-z |
| _version_ | 1818022804398800896 |
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| author | Qinwei Chen Suqi Deng Manman Deng Yuanfei Shi Mengya Zhong Lihong Ding Yuelong Jiang Yong Zhou Bing Z. Carter Bing Xu |
| author_facet | Qinwei Chen Suqi Deng Manman Deng Yuanfei Shi Mengya Zhong Lihong Ding Yuelong Jiang Yong Zhou Bing Z. Carter Bing Xu |
| author_sort | Qinwei Chen |
| collection | DOAJ |
| description | Abstract Dysregulation of MDM2, a p53 negative regulator, frequently occurs in acute myeloid leukemia (AML) and is associated with unfavorable prognoses, rendering the p53-MDM2 axis an attractive target for the development of small-molecule inhibitors. MDM2 antagonists have been intensely developed but only lead to limited clinical activity, suggesting combination with additional drugs is an unmet medical need. In this study, we reported that Triptolide synergized with MDM2 inhibitor Nutlin-3a to suppress cell proliferation and induce mitochondrial-mediated apoptosis in p53 wt AML in vitro and ex vivo. More importantly, Triptolide cooperated with Nutlin-3a to delay tumor growth and abrogate leukemia burden in an AML xenograft model. In addition, we observed that Triptolide and Nutlin-3a were also cooperative in part of p53 deficient cases. Mechanistically, Nutlin-3a upregulated the transcriptional expressions of the p53 downstream targets PUMA and p21, while Triptolide declined the mRNA levels of two anti-apoptotic factors, XIAP and Mcl-1, in p53 wt cells. These effects were more notable when Triptolide and Nutlin-3a were combined. Our results revealed that Triptolide monotherapy exerted its antileukemia effect via both p53-dependent and independent ways, with the latter through perturbation of the MYC-ATF4 axis-mediated ER stress. Collectively, these data suggested that the Triptolide-Nutlin-3a combination might be a novel potential therapeutic intervention for patients with AML and it warrants further clinical evaluations. |
| first_indexed | 2024-12-10T03:34:15Z |
| format | Article |
| id | doaj.art-c1fbba5b8da04b61859915b7ecb0f9dd |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-12-10T03:34:15Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-c1fbba5b8da04b61859915b7ecb0f9dd2022-12-22T02:03:45ZengBMCExperimental Hematology & Oncology2162-36192022-04-011111410.1186/s40164-022-00276-zTherapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathwaysQinwei Chen0Suqi Deng1Manman Deng2Yuanfei Shi3Mengya Zhong4Lihong Ding5Yuelong Jiang6Yong Zhou7Bing Z. Carter8Bing Xu9Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityDepartment of Pathology, The First Affiliated Hospital of Xiamen University and College of Medicine, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversitySection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer CenterDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen UniversityAbstract Dysregulation of MDM2, a p53 negative regulator, frequently occurs in acute myeloid leukemia (AML) and is associated with unfavorable prognoses, rendering the p53-MDM2 axis an attractive target for the development of small-molecule inhibitors. MDM2 antagonists have been intensely developed but only lead to limited clinical activity, suggesting combination with additional drugs is an unmet medical need. In this study, we reported that Triptolide synergized with MDM2 inhibitor Nutlin-3a to suppress cell proliferation and induce mitochondrial-mediated apoptosis in p53 wt AML in vitro and ex vivo. More importantly, Triptolide cooperated with Nutlin-3a to delay tumor growth and abrogate leukemia burden in an AML xenograft model. In addition, we observed that Triptolide and Nutlin-3a were also cooperative in part of p53 deficient cases. Mechanistically, Nutlin-3a upregulated the transcriptional expressions of the p53 downstream targets PUMA and p21, while Triptolide declined the mRNA levels of two anti-apoptotic factors, XIAP and Mcl-1, in p53 wt cells. These effects were more notable when Triptolide and Nutlin-3a were combined. Our results revealed that Triptolide monotherapy exerted its antileukemia effect via both p53-dependent and independent ways, with the latter through perturbation of the MYC-ATF4 axis-mediated ER stress. Collectively, these data suggested that the Triptolide-Nutlin-3a combination might be a novel potential therapeutic intervention for patients with AML and it warrants further clinical evaluations.https://doi.org/10.1186/s40164-022-00276-zAcute myeloid leukemia (AML)p53MDM2 inhibitorTriptolideMYCATF4 |
| spellingShingle | Qinwei Chen Suqi Deng Manman Deng Yuanfei Shi Mengya Zhong Lihong Ding Yuelong Jiang Yong Zhou Bing Z. Carter Bing Xu Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways Experimental Hematology & Oncology Acute myeloid leukemia (AML) p53 MDM2 inhibitor Triptolide MYC ATF4 |
| title | Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways |
| title_full | Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways |
| title_fullStr | Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways |
| title_full_unstemmed | Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways |
| title_short | Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways |
| title_sort | therapeutic synergy of triptolide and mdm2 inhibitor against acute myeloid leukemia through modulation of p53 dependent and independent pathways |
| topic | Acute myeloid leukemia (AML) p53 MDM2 inhibitor Triptolide MYC ATF4 |
| url | https://doi.org/10.1186/s40164-022-00276-z |
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