Combined treatment of leukemia cells with vitamin K2 and 1α,25-dihydroxy vitamin D3 enhances monocytic differentiation along with becoming resistant to apoptosis by induction of cytoplasmic p21CIP1

Iguchi,Tomotaka; Miyazawa,Keisuke; Asada,Minoru; Gotoh,Akihiko; Mizutani,Shuki; Ohyashiki,Kazuma

doi:10.3892/ijo.27.4.893

October 2005 Volume 27 Issue 4

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October 2005 Volume 27 Issue 4

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Article

Combined treatment of leukemia cells with vitamin K2 and 1α,25-dihydroxy vitamin D3 enhances monocytic differentiation along with becoming resistant to apoptosis by induction of cytoplasmic p21CIP1

Authors:
- Tomotaka Iguchi
- Keisuke Miyazawa
- Minoru Asada
- Akihiko Gotoh
- Shuki Mizutani
- Kazuma Ohyashiki
View Affiliations / Copyright

Affiliations: First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan
Pages: 893-900
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Published online on: October 1, 2005

https://doi.org/10.3892/ijo.27.4.893
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Abstract

Vitamin K2 (VK2) effectively induces apoptosis in leukemia cell lines, including HL-60 and U937. However, combined treatment of cells with VK2 plus 1α, 25-dihydroxy vitamin D3 (VD3) resulted in suppression of VK2-inducing apoptosis and pronounced induction of monocytic differentiation as compared with that by VD3 alone. After achieving monocytic differentiation by pre-exposure to VK2 and VD3, the cells became resistant to various apoptotic stimuli including VK2- and H2O2-treatment and serum deprivation. Accumulation of cytoplasm p21CIP1 along with disappearance of nuclear p21CIP1 was detected in cells in response to 96-h treatment with VK2 plus VD3. A stable transfectant, U937-ΔNLS-p21CIP1, which lacked the nuclear localization signal of p21CIP1 and showed overexpression of cytoplasm p21CIP1 without monocytic differentiation, was resistant to apoptosis. These data suggest that a change of intracellular distribution of p21CIP1 from nucleus to cytoplasm along with differentiation appears to be anti-apoptotic. Clinical benefits of using VK2 for treatment of patients with leukemia and myelodysplastic syndrome (MDS) have been reported. Our data suggest that VK2 plus VD3 may be an effective combination for differentiation-based therapy for leukemia and also MDS whose cytopenias are mediated though apoptosis.

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Combined treatment of leukemia cells with vitamin K2 and 1α,25-dihydroxy vitamin D3 enhances monocytic differentiation along with becoming resistant to apoptosis by induction of cytoplasmic p21CIP1

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