Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo
| Autor: | Chia-Wei Liu, Jia-Ming Chang, Jiann-Jyh Huang, Lynn Y L Huang, Shih-Hsien Chuang, Chia-chi Chang, Johnson Y.N. Lau, Pei-Yi Tsai, Kuo-Jang Kao, Her-Sheng Lin, Ying-Shuan Lee, Gillian M.G. Lau |
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| Rok vydání: | 2014 |
| Předmět: |
Niacinamide
Cancer Research Antineoplastic Agents Apoptosis Breast Neoplasms Pharmacology In Vitro Techniques Heterocyclic Compounds 4 or More Rings Mice Breast cancer In vivo Medicine Cytotoxic T cell Animals Humans Doxorubicin Molecular Targeted Therapy Cytotoxicity business.industry Cancer Nuclear Proteins medicine.disease Xenograft Model Antitumor Assays humanities Gene Expression Regulation Neoplastic Cytoskeletal Proteins Thiazoles Oncology Cell culture Drug Resistance Neoplasm MCF-7 Cells Topotecan Female business human activities medicine.drug |
| Zdroj: | Molecular cancer therapeutics. 13(6) |
| ISSN: | 1538-8514 |
| Popis: | Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI50 = 14.29–73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI50 > 10 μmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers. Mol Cancer Ther; 13(6); 1419–30. ©2014 AACR . This article is featured in Highlights of This Issue, [p. 1391][1] [1]: /lookup/volpage/13/1391?iss=6 |
| Databáze: | OpenAIRE |
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