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Combined antitumor activity of 7-Hydroxystaurosporine (UCN-01) and Tamoxifen against human breast carcinomain Vitro andin Vivo

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Abstract

Background

7-Hydroxystaurosporine (UCN-01) was originally isolated as a protein kinase C inhibitor and has shown antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1to the S phase and is associated with inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor p21, leading to dephosphorylation of retinoblastoma (Rb) protein. Tamoxifen (TAM) traps cancer cells in the Gl phase, suggesting that the mechanism of action of TAM is similar to that of UCN-01. The present study was conducted to assess the antitumor activity of UCN-01 combined with TAM against human breast carcinoma cellsin vitro andin vivo.

Materials and Methods

MCF-7 cells were treated with UCN-01, TAM, or UCN-01 combined with TAM at various concentrationsin vitro. The antitumor effect was evaluated as the inhibition rate (I.R.%) by MTT assay. Two human breast carcinoma xenografts in nude mice, MCF-7 and Br-10, were treated with UCN-01, TAM or both agents together. The expression of p21 and the phosphorylation status of Rb protein in MCF-7 cells were detected by Western blotting.

Results

UCN-01 or TAM alone inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. Combined treatment with UCN-01 followed by TAM inhibited the growth of MCF-7 cells synergistically and no significant differences in cytotoxicity were observed between the different sequences of UCN-01/TAM and TAM/UCN-01. Combination treatment with UCN-01 and TAM against MCF-7 and Br-10in vivo exhibited superior antitumor effects compared with either agent treatment alone. Although 0.1μg UCN-01 per ml (I.R.: 48.1%) or 2μM TAM (I.R.: 31%) induced p21 expression, phosphorylation of Rb protein was not inhibited. However, combination treatment with UCN-01 and TAM at the same concentrations resulted in an I.R. of 67% and dephosphorylation of Rb protein.

Conclusion

The present study suggests that combining UCN-01 and TAM could result in augmented cytotoxicity because of their similar mechanism of action. This combination may have potential clinical applications for breast cancer treatment, by reducing the toxicity of UCN-01.

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Abbreviations

PKC:

Protein kinase C

CDK:

Cyclin-dependent kinase

TAM:

Tamoxifen

pRb:

Retinoblastoma protein

ER:

Estrogen receptor

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Author information

Authors and Affiliations

  1. Departments of Surgery, Saitama Social Insurance Hospital, Japan

    Junichi Koh, Mitsumasa Hashimoto & Yoichiro Hosoda

  2. Department of Surgery, School of Medicine, Keio University, Japan

    Tetsuro Kubota & Masaki Kitajima

  3. Departments of Pathology, Saitama Social Insurance Hospital, Japan

    Toshiko Koyama & Tomofusa Migita

Authors
  1. Junichi Koh
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  2. Tetsuro Kubota
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  3. Toshiko Koyama
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  4. Tomofusa Migita
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  5. Mitsumasa Hashimoto
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  6. Yoichiro Hosoda
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  7. Masaki Kitajima
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Corresponding author

Correspondence to Junichi Koh.

Additional information

Reprint requests to Junichi Koh, Department of Surgery, Saitama Social Insurance Hospital, 4-9-3, Kitaurawa, Saitama-shi, Saitama 330-0074, Japan.

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Koh, J., Kubota, T., Koyama, T. et al. Combined antitumor activity of 7-Hydroxystaurosporine (UCN-01) and Tamoxifen against human breast carcinomain Vitro andin Vivo . Breast Cancer 10, 260–267 (2003). https://doi.org/10.1007/BF02966727

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  • DOI: https://doi.org/10.1007/BF02966727

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