| RRC ID |
69766
|
| 著者 |
Sumi K, Tago K, Nakazawa Y, Takahashi K, Ohe T, Mashino T, Funakoshi-Tago M.
|
| タイトル |
Novel Mechanism by a Bis-Pyridinium Fullerene Derivative to Induce Apoptosis by Enhancing the MEK-ERK Pathway in a Reactive Oxygen Species-Independent Manner in BCR-ABL-Positive Chronic Myeloid Leukemia-Derived K562 Cells.
|
| ジャーナル |
Int J Mol Sci
|
| Abstract |
In the treatment of breakpoint cluster region-Abelson (BCR-ABL)-positive chronic myeloid leukemia (CML) using BCR-ABL inhibitors, the appearance of a gatekeeper mutation (T315I) in BCR-ABL is a serious issue. Therefore, the development of novel drugs that overcome acquired resistance to BCR-ABL inhibitors by CML cells is required. We previously demonstrated that a bis-pyridinium fullerene derivative (BPF) induced apoptosis in human chronic myeloid leukemia (CML)-derived K562 cells partially through the generation of reactive oxygen species (ROS). We herein show that BPF enhanced the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase (MEK-ERK) pathway in a ROS-independent manner. BPF-induced apoptosis was attenuated by trametinib, suggesting the functional involvement of the MEK-ERK pathway in apoptosis in K562 cells. In addition, the constitutive activation of the MEK-ERK pathway by the enforced expression of the BRAFV600E mutant significantly increased the sensitivity of K562 cells to BPF. These results confirmed for the first time that BPF induces apoptosis in K562 cells through dual pathways—ROS production and the activation of the MEK-ERK pathway. Furthermore, BPF induced cell death in transformed Ba/F3 cells expressing not only BCR-ABL but also T315I mutant through the activation of the MEK-ERK pathway. These results indicate that BPF is as an effective CML drug that overcomes resistance to BCR-ABL inhibitors.
|
| 巻・号 |
23(2)
|
| 公開日 |
2022-1-11
|
| DOI |
10.3390/ijms23020749
|
| PII |
ijms23020749
|
| PMID |
35054935
|
| PMC |
PMC8775703
|
| MeSH |
Animals
Apoptosis / drug effects*
Fullerenes / chemistry
Fullerenes / pharmacology*
Fusion Proteins, bcr-abl / genetics*
Genes, Essential
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
MAP Kinase Signaling System / drug effects*
Mice
Models, Biological
Mutation
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Reactive Oxygen Species / metabolism*
|
| IF |
4.556
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
