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Article

Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract

  • Authors:
    • Hidetomo Kikuchi
    • Bo Yuan
    • Eisuke Yuhara
    • Masahiko Imai
    • Ryota Furutani
    • Shin Fukushima
    • Shingo Hazama
    • Chieko Hirobe
    • Kunio Ohyama
    • Norio Takagi
    • Hiroo Toyoda
  • View Affiliations / Copyright

    Affiliations: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan, Department of Cultural History, Seisen University, Shinagawa-ku, Tokyo 141-0022, Japan, Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
  • Pages: 843-852
    |
    Published online on: May 21, 2014
       https://doi.org/10.3892/ijo.2014.2454
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Abstract

We have demonstrated that an extract from the ripe fruit of Vitex angus-castus (Vitex), might be a promising anticancer candidate. In order to further provide a molecular rationale for clinical development in anticancer therapy, a detailed mechanism underlying the efficacy of Vitex against HL-60 cells was investigated. Vitex induced a dose- and time-dependent decrease in cell viability associated with induction of apoptosis and G2/M cell cycle arrest, both of which were suppressed by the addition of SB203580, an inhibitor for p38 MAPK. Furthermore, SB203580 significantly suppressed Vitex-induced phosphorylation of histone H3, a downstream molecule of p38 MAPK known to be involved in apoptosis induction in tumor cells. Notably, Vitex induced upregulation of intracellular ATP, known to bind its binding pocket inside activated p38 MAPK and to be required for the activation of p38 MAPK pathway. These results, thus, suggest that upregulation of intracellular ATP and phosphorylation of histone H3 are closely associated with the activation of p38 MAPK pathway, consequently contributing to Vitex-mediated cytotoxicity. Intriguingly, a significant decrease of intracellular ROS levels and downregulation of expression level of gp91phox, an important component of NADPH oxidase, were observed in Vitex-treated cells. A greater decline in ROS levels along with enhanced apoptosis was observed after treatment with Vitex in combination with SnPP, an inhibitor specific for HO-1. Since NADPH oxidase and HO-1 are closely correlated to redox status associated with intracellular ROS levels, the two enzymes are suggested to be implicated in Vitex-mediated cytotoxicity in HL-60 cells by regulating ROS generation. We also suggest that activation of the p38 MAPK pathway may be dependent on the alterations of intracellular ATP levels, rather than that of intracellular ROS levels. These results may have important implications for appropriate clinical uses of Vitex and provide novel insights into the interaction between Vitex and other conventional drugs capable of affecting intracellular redox status.
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Copy and paste a formatted citation
Spandidos Publications style
Kikuchi H, Yuan B, Yuhara E, Imai M, Furutani R, Fukushima S, Hazama S, Hirobe C, Ohyama K, Takagi N, Takagi N, et al: Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract. Int J Oncol 45: 843-852, 2014.
APA
Kikuchi, H., Yuan, B., Yuhara, E., Imai, M., Furutani, R., Fukushima, S. ... Toyoda, H. (2014). Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract. International Journal of Oncology, 45, 843-852. https://doi.org/10.3892/ijo.2014.2454
MLA
Kikuchi, H., Yuan, B., Yuhara, E., Imai, M., Furutani, R., Fukushima, S., Hazama, S., Hirobe, C., Ohyama, K., Takagi, N., Toyoda, H."Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract". International Journal of Oncology 45.2 (2014): 843-852.
Chicago
Kikuchi, H., Yuan, B., Yuhara, E., Imai, M., Furutani, R., Fukushima, S., Hazama, S., Hirobe, C., Ohyama, K., Takagi, N., Toyoda, H."Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract". International Journal of Oncology 45, no. 2 (2014): 843-852. https://doi.org/10.3892/ijo.2014.2454
Copy and paste a formatted citation
x
Spandidos Publications style
Kikuchi H, Yuan B, Yuhara E, Imai M, Furutani R, Fukushima S, Hazama S, Hirobe C, Ohyama K, Takagi N, Takagi N, et al: Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract. Int J Oncol 45: 843-852, 2014.
APA
Kikuchi, H., Yuan, B., Yuhara, E., Imai, M., Furutani, R., Fukushima, S. ... Toyoda, H. (2014). Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract. International Journal of Oncology, 45, 843-852. https://doi.org/10.3892/ijo.2014.2454
MLA
Kikuchi, H., Yuan, B., Yuhara, E., Imai, M., Furutani, R., Fukushima, S., Hazama, S., Hirobe, C., Ohyama, K., Takagi, N., Toyoda, H."Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract". International Journal of Oncology 45.2 (2014): 843-852.
Chicago
Kikuchi, H., Yuan, B., Yuhara, E., Imai, M., Furutani, R., Fukushima, S., Hazama, S., Hirobe, C., Ohyama, K., Takagi, N., Toyoda, H."Involvement of histone H3 phosphorylation via the activation of p38 MAPK pathway and intracellular redox status in cytotoxicity of HL-60 cells induced by Vitex agnus-castus fruit extract". International Journal of Oncology 45, no. 2 (2014): 843-852. https://doi.org/10.3892/ijo.2014.2454
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