Autor: |
Qingfeng Yu, Ping Wang, Linlin Yang, Zhaoxing Wu, Shu Li, Ying Xu, Bowen Wu, An Ma, Xiaoxian Gan, Rongzhen Xu |
Jazyk: |
angličtina |
Rok vydání: |
2019 |
Předmět: |
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Zdroj: |
Biomedicine & Pharmacotherapy, Vol 117, Iss , Pp - (2019) |
Druh dokumentu: |
article |
ISSN: |
0753-3322 |
DOI: |
10.1016/j.biopha.2019.109134 |
Popis: |
Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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