Inhibition of Hec1 as a novel approach for treatment of primary liver cancer
| Autor: | Chia-chi Chang, Jiann-Jyh Huang, Ying-Shuan Lee, Gillian M.G. Lau, Johnson Y.N. Lau, Her-Sheng Lin, Lynn Y L Huang, Robert G. Gish, Kuo-Jang Kao, Jia-Ming Chang, Shih-Hsien Chuang, Chia-Wei Liu, Pei-Yi Tsai |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Hepatoblastoma Antineoplastic Agents Apoptosis Mice SCID Protein Serine-Threonine Kinases Pharmacology Biology Toxicology Heterocyclic Compounds 4 or More Rings Mice In vivo Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Carcinoma medicine Animals Humans NIMA-Related Kinases Potency Pharmacology (medical) Molecular Targeted Therapy Cell Proliferation Regulation of gene expression Oncogene Liver Neoplasms Nuclear Proteins Cancer medicine.disease Xenograft Model Antitumor Assays humanities In vitro Gene Expression Regulation Neoplastic Cytoskeletal Proteins Oncology human activities |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 74:511-520 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | 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) (GI(50) 30-70 nM), which was superior to sorafenib and other cytotoxic agents. TAI-95 was relatively inactive in non-cancerous cell lines (GI(50)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. |
| Databáze: | OpenAIRE |
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