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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 9/2015

01-09-2015 | Hepatobiliary Tumors

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

Authors: Hiroko Matsunaga, MD, Shinji Tanaka, MD, PhD, FACS, 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

Published in: Annals of Surgical Oncology | Issue 9/2015

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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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Metadata
Title
A Novel Therapeutic Combination Sequentially Targeting Aurora B and Bcl-xL in Hepatocellular Carcinoma
Authors
Hiroko Matsunaga, MD
Shinji Tanaka, MD, PhD, FACS
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
Publication date
01-09-2015
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 9/2015
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-4292-3

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