The mechanisms of taxodione-induced apoptosis in BCR-ABL-positive leukemia cells

Yuki Uchihara, Kenji Tago, Megumi Tago

Research output: Contribution to journalArticle

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Abstract

Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are caused by a fusion protein, BCR-ABL, which induces cellular transformation by activating the signaling molecules, STAT5 and Akt. The specific BCR-ABL inhibitors including imatinib, nilotinib, and dasatinib, are clinically utilized in the treatment with CML and ALL patients. Although these BCR-ABL inhibitors are initially successful in the treatment of leukemia, many patients develop drug resistance due to the appearance of the gatekeeper mutation of BCR-ABL, T315I. Recently, we found that taxodione, a quinone methide diterpene isolated from a conifer, Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which is positive for the bcr-abl gene. Taxodione reduced the activities of mitochondrial respiratory chain complex III, leading to the production of reactive oxygen species (ROS). An antioxidant agent, N-acetylcysteine (NAC), canceled taxodione-induced ROS production and apoptotic cell death, suggesting that taxodione induced apoptosis through ROS accumulation. Furthermore, in K562 cells treated with taxodione, BCR-ABL, STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation. Strikingly, NAC canceled these taxodione-caused inhibition of BCR-ABL, STAT5 and Akt. In addition, taxodione significantly induced apoptosis in transformed Ba/F3 cells by not only BCR-ABL but also T315I-mutated BCR-ABL through the generation of ROS, suggesting that taxodione has potential as anti-tumor drug with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells. It's also expected that these knowledge becomes an important clue in the development of anti-cancer drugs against the broad range of tumors.

Original languageEnglish
Pages (from-to)147-154
Number of pages8
JournalNihon yakurigaku zasshi. Folia pharmacologica Japonica
Volume153
Issue number4
DOIs
Publication statusPublished - 2019 Jan 1

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Leukemia
Apoptosis
Reactive Oxygen Species
K562 Cells
Acetylcysteine
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Taxodium
abl Genes
Coniferophyta
Neoplasms
Mutation
Myeloid Leukemia
taxodione
Diterpenes
Electron Transport Complex III
Electron Transport
Drug Resistance
Pharmaceutical Preparations
Cell Death

ASJC Scopus subject areas

  • Pharmacology

Cite this

The mechanisms of taxodione-induced apoptosis in BCR-ABL-positive leukemia cells. / Uchihara, Yuki; Tago, Kenji; Tago, Megumi.

In: Nihon yakurigaku zasshi. Folia pharmacologica Japonica, Vol. 153, No. 4, 01.01.2019, p. 147-154.

Research output: Contribution to journalArticle

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