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A Novel Therapeutic Combination Sequentially Targeting Aurora B and Bcl-xL in Hepatocellular Carcinoma

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

ABSTRACT

Background

Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition.

Methods

This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models.

Results

The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy.

Conclusion

Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors’ preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.

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Acknowledgment

We thank AstraZeneca for kindly providing us with AZD1152 and AZD1152-HQPA for experimental studies. We also thank Drs. Andrew Foxley and Kate Owen (AstraZeneca) for their helpful review of our manuscript. This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas; Scientific Research (A) from the Ministry of Education, Culture, Sports, Science & Technology of Japan; and a Health & Labour Sciences Research Grant from the Ministry of Health Labour & Welfare of Japan.

Disclosure

Hiroko Matsunaga, Shinji Tanaka, Arihiro Aihara, Kousuke Ogawa, Satoshi Matsumura, Daisuke Ban, Takanori Ochiai, Takumi Irie, Atsushi Kudo, Noriaki Nakamura, Shigeki Arii and Minoru Tanabe declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Hiroko Matsunaga MD, Arihiro Aihara MD, PhD, Kousuke Ogawa MD, PhD, Satoshi Matsumura MD, PhD, Daisuke Ban MD, PhD, Takanori Ochiai MD, PhD, Takumi Irie MD, PhD, Atsushi Kudo MD, PhD, Noriaki Nakamura MD, PhD, Shigeki Arii MD, PhD & Minoru Tanabe MD, PhD

  2. Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Shinji Tanaka MD, PhD, FACS

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  1. Hiroko Matsunaga MD
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  2. Shinji Tanaka MD, PhD, FACS
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  3. Arihiro Aihara MD, PhD
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  4. Kousuke Ogawa MD, PhD
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  5. Satoshi Matsumura MD, PhD
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  12. Minoru Tanabe MD, PhD
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Correspondence to Shinji Tanaka MD, PhD, FACS.

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Matsunaga, H., Tanaka, S., Aihara, A. et al. A Novel Therapeutic Combination Sequentially Targeting Aurora B and Bcl-xL in Hepatocellular Carcinoma. Ann Surg Oncol 22, 3079–3086 (2015). https://doi.org/10.1245/s10434-014-4292-3

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  • DOI: https://doi.org/10.1245/s10434-014-4292-3

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