Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis

Paul J. Davis, Hung Yun Lin, Thangirala Sudha, Murat Yalcin, Heng Yuan Tang, Aleck Hercbergs, John T. Leith, Mary K. Luidens, Osnat Ashur-Fabian, Sandra Incerpi, Shaker A. Mousa

Research output: Contribution to journalReview article

30 Citations (Scopus)

Abstract

The extracellular domain of integrin avB3 contains a receptor for thyroid hormone and hormone analogs. The integrin is amply expressed by tumor cells and dividing blood vessel cells. The proangiogenic properties of thyroid hormone and the capacity of the hormone to promote cancer cell proliferation are functions regulated nongenomically by the hormone receptor on avB3. An L-thyroxine (T4) analog, tetraiodothyroacetic acid (tetrac), blocks binding of T4 and 3,5,3'-triiodo-L-thyronine (T3) by avB3 and inhibits angiogenic activity of thyroid hormone. Covalently bound to a 200 nm nanoparticle that limits its activity to the cell exterior, tetrac reformulated as Nanotetrac has additional effects mediated by avB3 beyond the inhibition of binding of T4 and T3 to the integrin. These actions of Nanotetrac include disruption of transcription of cell survival pathway genes, promotion of apoptosis by multiple mechanisms, and interruption of repair of double-strand deoxyribonucleic acid breaks caused by irradiation of cells. Among the genes whose expression is suppressed by Nanotetrac are EGFR, VEGFA, multiple cyclins, catenins, and multiple cytokines. Nanotetrac has been effective as a chemotherapeutic agent in preclinical studies of human cancer xenografts. The low concentrations of avB3 on the surface of quiescent nonmalignant cells have minimized toxicity of the agent in animal studies.

Original languageEnglish
Pages (from-to)1619-1624
Number of pages6
JournalOncoTargets and Therapy
Volume7
DOIs
Publication statusPublished - 2014

Keywords

  • Antiangiogenesis
  • Integrin
  • Proapoptosis
  • Thyroid hormone
  • Thyroxine

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

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