Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells

Miki Takeuchi, Eishi Ashihara, Yohko Yamazaki, Shinya Kimura, Yoko Nakagawa, Ruriko Tanaka, Hisayuki Yao, Rina Nagao, Yoshihiro Hayashi, Hideyo Hirai, Taira Maekawa

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Treatment with Abl tyrosine kinase inhibitors (TKI) drastically improves the prognosis of chronic myelogenous leukemia (CML) patients. However, quiescent CML cells are insensitive to TKI and can lead to relapse of the disease. Thus, research is needed to elucidate the properties of these quiescent CML cells, including their microenvironment, in order to effectively target them. Hypoxia is known to be a common feature of solid tumors that contributes to therapeutic resistance. Leukemic cells are also able to survive and proliferate in severely hypoxic environments. The hypoxic conditions in the bone marrow (BM) allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. A previous report showed that Rakicidin A, a natural product produced by the Micromonospora strain, induced hypoxia-selective cytotoxicity in solid tumors. Here, we describe Rakicidin A-induced cell death in hypoxia-adapted (HA)-CML cells with stem cell-like characteristics. Interestingly, apoptosis was induced via caspase-dependent and -independent pathways. In addition, treatment with Rakicidin A in combination with the TKI, imatinib, resulted in synergistic cytotoxicity against HA-CML cells. In conclusion, Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic BM environment.

Original languageEnglish
Pages (from-to)591-596
Number of pages6
JournalCancer Science
Volume102
Issue number3
DOIs
Publication statusPublished - Mar 1 2011
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Apoptosis
Protein-Tyrosine Kinases
Cell Death
Stem Cells
Micromonospora
Bone Marrow
Cytotoxins
Caspases
Hypoxia
rakicidin A
Biological Products
Neoplasms
Therapeutics
Recurrence
Research

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Takeuchi, M., Ashihara, E., Yamazaki, Y., Kimura, S., Nakagawa, Y., Tanaka, R., ... Maekawa, T. (2011). Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. Cancer Science, 102(3), 591-596. https://doi.org/10.1111/j.1349-7006.2010.01813.x

Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. / Takeuchi, Miki; Ashihara, Eishi; Yamazaki, Yohko; Kimura, Shinya; Nakagawa, Yoko; Tanaka, Ruriko; Yao, Hisayuki; Nagao, Rina; Hayashi, Yoshihiro; Hirai, Hideyo; Maekawa, Taira.

In: Cancer Science, Vol. 102, No. 3, 01.03.2011, p. 591-596.

Research output: Contribution to journalArticle

Takeuchi, M, Ashihara, E, Yamazaki, Y, Kimura, S, Nakagawa, Y, Tanaka, R, Yao, H, Nagao, R, Hayashi, Y, Hirai, H & Maekawa, T 2011, 'Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells', Cancer Science, vol. 102, no. 3, pp. 591-596. https://doi.org/10.1111/j.1349-7006.2010.01813.x
Takeuchi M, Ashihara E, Yamazaki Y, Kimura S, Nakagawa Y, Tanaka R et al. Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. Cancer Science. 2011 Mar 1;102(3):591-596. https://doi.org/10.1111/j.1349-7006.2010.01813.x
Takeuchi, Miki ; Ashihara, Eishi ; Yamazaki, Yohko ; Kimura, Shinya ; Nakagawa, Yoko ; Tanaka, Ruriko ; Yao, Hisayuki ; Nagao, Rina ; Hayashi, Yoshihiro ; Hirai, Hideyo ; Maekawa, Taira. / Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells. In: Cancer Science. 2011 ; Vol. 102, No. 3. pp. 591-596.
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