International Journal of Hematology

, Volume 78, Issue 3, pp 219–225 | Cite as

N-(4-Hydroxyphenyl)retinamide (4-HPR) Induces Leukemia Cell Death via Generation of Reactive Oxygen Species

  • Hiroaki Goto
  • Hiroyuki Takahashi
  • Hisaki Fujii
  • Koichiro Ikuta
  • Shumpei Yokota
Progress in Hematology

Abstract

The role of reactive oxygen species (ROS) in the cytotoxicity of N-(4-hydroxyphenyl)retinamide (4-HPR) was studied with use of the B-precursor lymphoblastic leukemia cell line YCUB-2. The increase in intracellular ROS measured with 2′-7′-dichlorodihydrofluorescein diacetate after 3 hours’ incubation was 3.7-fold with 1 μM 4-HPR and 5.8-fold with 5 μM 4-HPR. The rate of apoptosis after 48 hours’ incubation was 9.8% and 56.4% in comparison with untreated cells. Hydroethidine, which is a more specific indicator of superoxide anion radical level, did not effectively detect 4-HPR-induced ROS. The antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one suppressed 4-HPR-induced ROS production and apoptosis. The cytotoxicity of 4-HPR was analyzed in 4 other leukemia/lymphoma lines (CCRF-HSB2, Molt-4, KG-1, HL-60). We found that the cytotoxicity of 4-HPR correlated with the amount of ROS produced in cell lines, except in HL-60 cells. The intracellular glutathione level varied among the 5 cell lines, the highest levels occurring in Molt-4 and KG-1, which were less sensitive to 4-HPR. Suppression of glutathione by buthionine sulfoximine enhanced the level of 4-HPR-induced ROS production and apoptosis in Molt-4. Our findings suggest that ROS play a significant role in the antileukemia effect of 4-HPR and that the glutathione level in leukemias may be associated the sensitivity of the cells to 4-HPR.

Key words

Fenretinide 4-HPR Leukemia ROS Glutathione 

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Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  • Hiroaki Goto
    • 1
  • Hiroyuki Takahashi
    • 1
  • Hisaki Fujii
    • 1
  • Koichiro Ikuta
    • 1
  • Shumpei Yokota
    • 1
  1. 1.Department of PediatricsYokohama City University School of MedicineYokohamaJapan

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