A bis-pyridinium fullerene derivative induces apoptosis through the generation of ROS in BCR-ABL-positive leukemia cells

Kazuya Sumi, Kenji Tago, Yosuke Nakazawa, Kyoko Takahashi, Tomoyuki Ohe, Tadahiko Mashino, Megumi Funakoshi-Tago

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 BCR-ABL 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.

Original languageEnglish
Article number174714
JournalEuropean journal of pharmacology
Volume916
DOIs
Publication statusPublished - 2022 Feb 5

Keywords

  • Acute lymphocytic leukemia (ALL)
  • BCR-ABL
  • Bis-pyridinium fullerene derivative (BPF)
  • Chronic myeloid leukemia (CML)
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Pharmacology

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