Oncotarget

Research Papers:

Synergistic effect of farnesyl transferase inhibitor lonafarnib combined with chemotherapeutic agents against the growth of hepatocellular carcinoma cells

Jialiang Wang, Yifan Lian, Yurong Gu, Hongbo Wang, Lin Gu, Yanlin Huang, Liang Zhou and Yuehua Huang _

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Oncotarget. 2017; 8:105047-105060. https://doi.org/10.18632/oncotarget.22086

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Abstract

Jialiang Wang1,*, Yifan Lian1,*, Yurong Gu1,2,*, Hongbo Wang1, Lin Gu1, Yanlin Huang2, Liang Zhou2 and Yuehua Huang1,2

1Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

*These authors contributed equally to this work

Correspondence to:

Yuehua Huang, email: huangyh53@mail.sysu.edu.cn

Keywords: lonafarnib; hepatocellular carcinoma; synergistic effect; chemoresistance

Received: April 21, 2017     Accepted: October 12, 2017     Published: October 26, 2017

ABSTRACT

Hepatocellular carcinoma (HCC) is a common and deadly cancer worldwide and is often refractory to chemotherapy due to the development of multidrug resistance. Lonafarnib is an orally active and potent non-peptidomimetic inhibitor of farnesyl transferase. Here, using in vitro HCC cell models, we demonstrated that lonafarnib inhibited tumor proliferation and reduced the activity of mitogen-activated protein kinases pathways. In addition, lonafarnib caused G1 to S phase arrest through the downregulation of Cyclin D1, CDK6 and SKP2, while it induced cellular apoptosis by promoting the cleavage and activation of Caspase-3 and PARP. When combined with doxorubicin and sorafenib, lonafarnib was able to increase the sensitivity of HCC cells to chemotherapy. Furthermore, we also constructed ABCB1-overexpressing HCC cells and found that lonafarnib decreased chemoresistance by inhibiting ABCB1-mediated drug efflux activity. These results suggest that lonafarnib may be a promising synergistic agent for improving the treatment of drug-resistant HCC.


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