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Biological effects of a relatively low concentration of 1-b-D-arabinofuranosylcytosine in K562 cells: Alterations of the cell cycle, erythroid-differentiation, and apoptosis

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Abstract

Therapeutic strategies for leukemia are directed to induction of differentiation and apoptosis as well as growth inhibition. One of the key antileukemic agents, 1-β-D-arabinofuranosylcytosine (ara C), is clinically applied according to these therapeutic aims. However, the molecular effects of 0.1 μg/ml of ara C, a concentration that corresponds to the serum level in leukemic patients on a conventional dose of ara C, have not been well disclosed. Here, we addressed these issues using K562 cells which derived from a blastic crisis of chronic myeloid leukemia. DNA synthesis of treated cells was suppressed from 1-6 h. But, it recovered at 12 h and no further inhibition was observed. The number of cells was not decreased but DNA fragmentation was observed at 72 h. The number of erythroid-differentiated cells also increased to 30% at 72 h. Along with treatment, no marked alteration of mRNAs for cell cycle-regulating genes was found and the retinoblastoma gene product remained hyperphosphorylated throughout treatment. The expression of mRNAs for apoptosis-regulating genes also remained unchanged, except for slight down-regulation of Bax. c-myc protein was not found later than 48 h, and Max mRNA was downregulated. c-jun was immediately induced, followed by the fluctuated expression level along with treatment. These findings suggest that the 0.1 μg/ml ara C changed the proliferation, differentiation and death of K562 cells in a biphasic manner. In the early phase, DNA synthesis was inhibited without altering the expression of cell cycle regulating-genes. In the latter phase, cell death and erythroid- differentiation occurred in accordance with the down-regulation of c-myc.

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Authors and Affiliations

  1. Department of Internal Medicine (IV), Aoto Hospital, The Jikei University School of Medicine, Tokyo, 125, Japan

    Hisashi Yamada, Junko Horiguchi-Yamada, Makoto Nagai, Shinobu Takahara, Tetsuaki Sekikawa, Takeshi Kawano, Kiyoshi Itoh, Sachiko Fukumi & Satsuki Iwase

  2. Department of Molecular Genetics, Institute of DNA Medicine, The Jikei University School of Medicine, 3-25-8 NishiShinbashi, IVEnato-ku, Tokyo, 105, Japan

    Hisashi Yamada

  3. Department of Oncology, Institute of DNA Medicine, The Jikei University School of Medicine, 3-25-8 NishiShinbashi, IVEnato-ku, Tokyo, 105, Japan

    Junko Horiguchi-Yamada

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  1. Hisashi Yamada
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Yamada, H., Horiguchi-Yamada, J., Nagai, M. et al. Biological effects of a relatively low concentration of 1-b-D-arabinofuranosylcytosine in K562 cells: Alterations of the cell cycle, erythroid-differentiation, and apoptosis. Mol Cell Biochem 187, 211–220 (1998). https://doi.org/10.1023/A:1006874931249

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