Inhibition of Hec1 as a novel approach for treatment of primary liver cancer

Cancer Chemotherapy and Pharmacology - 2014
Lynn YL Huang1, Chia-chi Chang1, Ying-Shuan Lee2, Jiann-Jyh Huang2, Shih-Hsien Chuang2, Jia-Ming Chang2, Kuo-Jang Kao1, Gillian MG Lau1, Pei-Yi Tsai2, Chia-wei Liu2, Her-Sheng Lin2, Robert G. Gish3,1, Johnson YN Lau1
1Taivex Therapeutics Corporation, Taipei City, Taiwan, ROC
2Development Center for Biotechnology, New Taipei City, Taiwan, ROC
3University of California, San Diego, La Jolla, USA

Tóm tắt

Highly expressed in cancer protein 1 (Hec1) is an oncogene and a promising molecular target for novel anticancer drugs. The purpose of this study was to evaluate the potential of a Hec1 inhibitor, TAI-95, as a treatment for primary liver cancer. In vitro and in vivo methods were used to test the activity of TAI-95. Gene expression analysis was used to evaluate clinical correlation of the target. In vitro growth inhibition results showed that TAI-95 has excellent potency on a wide range of primary liver cancer cell lines (hepatoblastoma or hepatocellular carcinoma) (GI50 30–70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI50 > 10 μM). TAI-95 disrupts the interaction between Hec1 and Nek2 and leads to degradation of Nek2, chromosomal misalignment, and apoptotic cell death. TAI-95 showed synergistic activity in selected cancer cell lines with doxorubicin, paclitaxel, and topotecan, but not with sorafenib. TAI-95 shows excellent potency in a Huh-7 xenograft mouse model when administered orally. Gene expression analysis of clinical samples demonstrated increased expression of Hec1/NDC80 and associated genes (Nek2, SMC1A, and SMC2) in 27 % of patients, highlighting the potential for using this therapeutic approach to target patients with high Hec1 expression. Inhibition of Hec1 using small molecule approach may represent a promising novel approach for the treatment of primary liver cancers.

Từ khóa


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