期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 916, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174714
关键词
Bis-pyridinium fullerene derivative (BPF); BCR-ABL; Chronic myeloid leukemia (CML); Acute lymphocytic leukemia (ALL); Reactive oxygen species (ROS)
This study demonstrated that a bis-pyridinium fullerene derivative (BPF) effectively induced apoptosis in CML and ALL cells through ROS generation, and reduced the expression of BCR-ABL, including the resistant mutant form.
A fusion protein, Breakpoint cluster region-Abelson (BCR-ABL) is responsible for the development of chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL). Inhibitors against BCR-ABL are effective for the treatment of leukemia; however, a gatekeeper mutation (T315I) in BCR-ABL results in resistance to these inhibitors, which markedly impedes their efficacy. We herein demonstrated that a bis-pyridinium fullerene derivative (BPF) significantly induced apoptosis in human CML-derived K562 cells and ALL-derived SUP-B15 cells via the generation of reactive oxygen species (ROS). BPF reduced the expression of Bcr-Abl mRNA by inhibiting expression of c-Myc through ROS production. BPF also accelerated protein degradation of BCR-ABL through ROS production. Furthermore, BPF down-regulated the expression of not only BCR-ABL but also T315I-mutated BCRABL in ROS-dependent manner. As a result, BPF effectively induced apoptosis in transformed Ba/F3 cells expressing both BCR-ABL and T315I-mutated BCR-ABL. Collectively, these results indicate the potential of BPF as an effective leukemia drug that overcomes resistance to BCR-ABL inhibitors.
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