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.

The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

“…These results are consistent with our recently reported work in which a reduction of host circulating T4 levels postponed clinical progression of a variety of aggressive solid tumors, including two cases of ovarian cancer. 90 Using pharmacological inhibitors of the hormonal receptor site on the αvβ3 integrin, which were developed by our group, we were able to abrogate an array of signaling events in various cancer cells in vitro 29,30,91,92 and extend survival in vivo. 93,94 Additional novel agents are under investigation (unpublished data).…”

Near‐infrared fluorescent peptide probes for imaging of tumor in vivo and their biotoxicity evaluation

“…It have been reported that the integrin αvβ3 expression correlates well with tumor progression and invasiveness of many tumor types . The highly restricted expression of integrin αvβ3 in rapidly growing and metastatic tumors makes these receptors interesting target for the detection of tumors . For this purpose, many molecular probes have been presented for imaging integrin expression using different modalities such as ultrasound, magnetic resonance imaging, positron emission tomography, and optical imaging .…”

“…6,7 The highly restricted expression of integrin avb3 in rapidly growing and metastatic tumors makes these receptors interesting target for the detection of tumors. [8][9][10] For this purpose, many molecular probes have been presented for imaging integrin expression using different modalities such as ultrasound, 11 magnetic resonance imaging, 12 positron emission tomography, 13 and optical imaging. 14 Arginine-Glycine-Aspartic (RGD) as a cell adhesion motif displayed on ECM or some proteins is the specific recognition site of integrins with theirs ligands, and this specific RGDintegrin system is widely used to monitor cell recognition and targeting.…”

Hormony tarczycy w ośrodkowym układzie nerwowym (OUN) i ich wpływ na nowotworzenie, zwłaszcza na rozwój i przebieg glioblastoma multiforme — hipoteza badawcza

“…The effects of thyroid hormone activity via interactions with integrin receptor can be blocked or even "reversed" by the application of thyroxine deaminated metabolite TRAK. The studies conducted to date indicate that this metabolite blocks alfavBeta3 receptor reactions, both with T3 and with T4, and consequently blocks vascular endothelial growth factor (VEGF) as well as the activity of basic fibroblast growth factor (bFGF) and, finally, decreases EGFR gene transcription [60,61]. The role of thyroid hormones in GBM (as previously mentioned) is also confirmed by the fact that pharmacologically evoked hypothyroidism led to more than two-year regression of GBM located in the optic chiasm and significantly prolonged the patient's life [19].…”

“…Efekty działania hormonów tarczycy przez interakcje z receptorem integrynowym mogą być zablokowane, a nawet "odwrócone" przez podanie zdeaminowanego metabolitu tyroksyny TRAK. Dotychczasowe badania wskazują, że metabolit ten blokuje reakcje alfaVBeta3 receptora zarówno z T3, jak i z T4 i w następstwie blokuje aktywność czynnika wzrostu śródbłonka naczyniowego (VEGF, vascular endothelial growth factor) i blokuje również aktywność zasadowego czynnika wzrostu fibroblastów (bFGF, basic fibroblast growth factor) i wreszcie obniża transkrypcję genu EGFR [60,61]. Rolę hormonów tarczycy w GBM (jak już poprzednio wspomniano) potwierdza również fakt, że wywołana farmakologicznie niedoczynność tarczycy doprowadziła do ponad 2-letniej regresji GBM zlokalizowanego w skrzyżowaniu nerwów ocznych i znacząco wydłużyła życia chorego [19].…”