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

作者：Huang Lynn Y L^*; Chang Chia Chi; Lee Ying Shuan; Chang Jia Ming; Huang Jiann Jyh; Chuang Shih Hsien; Kao Kuo Jang; Lau Gillian M G; Tsai Pei Yi; Liu Chia Wei; Lin Her Sheng; Lau Johnson Y N

来源：Molecular Cancer Therapeutics, 2014, 13(6): 1419-1430.

DOI：10.1158/1535-7163.MCT-13-0700

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 (GI(50) = 14.29- 73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI50 > 10 mu mol/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.

• 出版日期2014-6