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Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model

  • Original Article – Clinical Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

A previous study showed that flavopiridol increased doxorubicin sensitivity in hypoxic hepatocellular carcinoma (HCC) cells by increasing apoptosis through suppressing hypoxia-inducible N-myc downstream-regulated gene-1 (NDRG1) expression. However, this has not been investigated in an in vivo HCC model. Therefore, we aimed to elucidate whether the combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model.

Methods

An HCC mouse model was established by implanting C3H/He mouse with MH134 cells. Then, doxorubicin with or without flavopiridol was injected. The anti-tumor efficacy was assessed by evaluating tumor volumes, and the underlying mechanism was investigated by quantifying apoptotic cells, the Ki-67 proliferation index, and microvessel densities (MVDs). Immunohistochemistry of NDRG1 was performed to determine the underlying mechanism.

Results

Tumor growth was significantly suppressed in the doxorubicin + flavopiridol combination group compared to the other three groups. The percentage of apoptotic cells was significantly higher, and Ki-67-positive proliferating cells were significantly lower in the combination group compared to the other groups; however, MVDs were not significantly different across the groups. Increased apoptosis by flavopiridol occurred by suppressing hypoxia-inducible NDRG1 expression.

Conclusions

These results show that a combination of doxorubicin and flavopiridol has a synergistic anti-tumor effect in an in vivo HCC model. This synergistic effect of combination therapy was attributed to increased apoptosis and decreased proliferation of tumor cells rather than decreased angiogenesis. These findings suggest that flavopiridol might be an effective adjuvant therapy to doxorubicin-resistant HCC cells by inducing apoptosis through suppression of NDRG1 expression.

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Abbreviations

HCC:

Hepatocellular carcinoma

TACE:

Transarterial chemoembolization

NDRG1:

N-myc downstream-regulated gene-1

NONMEM:

Nonlinear mixed effect modeling

MVD:

Microvessel density

H&E:

Hematoxylin and eosin

HIF-1α:

Hypoxia-inducible factor-1α

HK II:

Hexokinase II

SD:

Standard deviations

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Acknowledgments

This study was funded by the Liver Research Foundation of Korea. The funding organizations had no role in the study design; collection, analysis, and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. Authors have full control of all primary data and that authors agree to allow the journal to review these data if requested.

Conflict of interest

The authors declare that they have no conflict of interest.

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Author notes

    Authors and Affiliations

    1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul, 110-744, Korea

      Min-Sun Kwak, Su Jong Yu, Jung-Hwan Yoon, Sung-Hee Lee, Soo-Mi Lee, Jeong-Hoon Lee, Yoon Jun Kim, Hyo-Suk Lee & Chung Yong Kim

    2. Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Korea

      Min-Sun Kwak

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    1. Min-Sun Kwak
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    Correspondence to Jung-Hwan Yoon.

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    Min-Sun Kwak and Su Jong Yu have contributed equally to this article.

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    Kwak, MS., Yu, S.J., Yoon, JH. et al. Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model. J Cancer Res Clin Oncol 141, 2037–2045 (2015). https://doi.org/10.1007/s00432-015-1990-6

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    • DOI: https://doi.org/10.1007/s00432-015-1990-6

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