Activity of a novel Hec1-targeted anticancer compound against breast cancer cell lines in vitro and in vivo.
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 (GI(50) > 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.
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan lynnhuang.lh245@gmail.com.
Lynn Y L
LY
Huang
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Chia-Chi
CC
Chang
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Ying-Shuan
YS
Lee
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Jia-Ming
JM
Chang
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Jiann-Jyh
JJ
Huang
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Shih-Hsien
SH
Chuang
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Kuo-Jang
KJ
Kao
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Gillian M G
GM
Lau
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Pei-Yi
PY
Tsai
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Chia-Wei
CW
Liu
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Her-Sheng
HS
Lin
Authors' Affiliations: Taivex Therapeutics Corporation, Taipei; and Development Center for Biotechnology, New Taipei City, Taiwan.
Johnson Y N
JY
Lau
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003598:Cytoskeletal Proteins; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D051379:Mice; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D013844:Thiazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C120529:NDC80 protein, human; D009687:Nuclear Proteins; C000592509:TA I-95; D013844:Thiazoles; D009536:Niacinamide; D004317:Doxorubicin