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ABT-263 sensitizes TRAIL-resistant hepatocarcinoma cells by downregulating the Bcl-2 family of anti-apoptotic protein

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Abstract

Purpose

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its selective cytotoxicity to transformed cells. However, most human hepatocellular carcinomas (HCC) develop resistance to TRAIL. Thus, there is an urgent need to investigate the molecular targets and the underlying mechanisms that may be involved in overriding the resistance of tumor cells to TRAIL.

Methods

Cell viability analysis was performed in HCC cells after treatment with TRAIL and/or ABT-263. Flow cytometry was used to assess apoptosis. The expression of caspases and members of the Bcl-2 family was examined through immunoblot analysis. Finally, the viability of cancer cells transfected with a plasmid containing HBx (hepatitis B virus X protein) following treatment with TRAIL was also measured.

Results

In this study, we demonstrate that ABT-263, a potent and orally bioavailable inhibitor of the Bcl-2 family, was able to reverse the resistance of hepatocarcinoma cell lines to TRAIL-induced apoptosis, while sparing normal liver cells. The molecular mechanism of the reversal in resistance may be attributed to the inhibition by ABT-263 of anti-apoptosis proteins of the Bcl-2 family. In addition, we determined that HBx was able to sensitize TRAIL-resistant hepatocarcinoma Huh7 cells.

Conclusions

These findings provide a novel insight into the clinical application of TRAIL-induced apoptosis of HCC cells.

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Acknowledgments

This work was supported by the Chinese National Fund for Fostering Talents of Basic Sciences (J1103513), the National Nature Science Foundation of China (81072151), the National Basic Research Program of China (2010CB529800), the Chinese 111 project (B06018) and the Fundamental Research Funds for the Central Universities program (3081009).

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  1. College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Guan Wang, Yao Zhan, Haiqing Wang & Wenhua Li

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  1. Guan Wang
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  2. Yao Zhan
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Correspondence to Wenhua Li.

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Wang, G., Zhan, Y., Wang, H. et al. ABT-263 sensitizes TRAIL-resistant hepatocarcinoma cells by downregulating the Bcl-2 family of anti-apoptotic protein. Cancer Chemother Pharmacol 69, 799–805 (2012). https://doi.org/10.1007/s00280-011-1763-0

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  • DOI: https://doi.org/10.1007/s00280-011-1763-0

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