title: Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis.
abstract: The extracellular domain of integrin αvβ3 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 αvβ3. An L-thyroxine (T4) analog, tetraiodothyroacetic acid (tetrac), blocks binding of T4 and 3,5,3'-triiodo-L-thyronine (T3) by αvβ3 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 αvβ3 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 αvβ3 on the surface of quiescent nonmalignant cells have minimized toxicity of the agent in animal studies.
authors.affiliation: Department of Medicine, Albany Medical College, Albany, NY, USA ; Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA ; PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Thangirala
authors.initials: T
authors.lastname: Sudha
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA ; Department of Physiology, Veterinary Medicine Faculty, Uludag University, Gorukle, Bursa, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Yalcin
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Tang
authors.affiliation: Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Aleck
authors.initials: A
authors.lastname: Hercbergs
authors.affiliation: Rhode Island Nuclear Science Center, Narragansett, RI, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Leith
authors.affiliation: Department of Medicine, Albany Medical College, Albany, NY, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Luidens
authors.affiliation: Translational Hemato-oncology Laboratory, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel ; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Ashur-Fabian
authors.affiliation: Department of Sciences, University of Roma Tre, Rome, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Incerpi
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
keywords: antiangiogenesis; integrin; proapoptosis; thyroid hormone; thyroxine