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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo

Lynn Y.L. Huang, Chia-Chi Chang, Ying-Shuan Lee, Jia-Ming Chang, Jiann-Jyh Huang, Shih-Hsien Chuang, Kuo-Jang Kao, Gillian M.G. Lau, Pei-Yi Tsai, Chia-Wei Liu, Her-Sheng Lin and Johnson Y.N. Lau
Lynn Y.L. Huang
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Chia-Chi Chang
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Ying-Shuan Lee
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Jia-Ming Chang
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Jiann-Jyh Huang
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Shih-Hsien Chuang
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Kuo-Jang Kao
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Gillian M.G. Lau
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Pei-Yi Tsai
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Chia-Wei Liu
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Her-Sheng Lin
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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Johnson Y.N. Lau
1Taivex Therapeutics Corporation, Taipei; and 2Development Center for Biotechnology, New Taipei City, Taiwan
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DOI: 10.1158/1535-7163.MCT-13-0700 Published June 2014
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Abstract

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

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received August 28, 2013.
  • Revision received March 7, 2014.
  • Accepted March 20, 2014.
  • ©2014 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 13 (6)
June 2014
Volume 13, Issue 6
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Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo
Lynn Y.L. Huang, Chia-Chi Chang, Ying-Shuan Lee, Jia-Ming Chang, Jiann-Jyh Huang, Shih-Hsien Chuang, Kuo-Jang Kao, Gillian M.G. Lau, Pei-Yi Tsai, Chia-Wei Liu, Her-Sheng Lin and Johnson Y.N. Lau
Mol Cancer Ther June 1 2014 (13) (6) 1419-1430; DOI: 10.1158/1535-7163.MCT-13-0700

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Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo
Lynn Y.L. Huang, Chia-Chi Chang, Ying-Shuan Lee, Jia-Ming Chang, Jiann-Jyh Huang, Shih-Hsien Chuang, Kuo-Jang Kao, Gillian M.G. Lau, Pei-Yi Tsai, Chia-Wei Liu, Her-Sheng Lin and Johnson Y.N. Lau
Mol Cancer Ther June 1 2014 (13) (6) 1419-1430; DOI: 10.1158/1535-7163.MCT-13-0700
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