Tetraiodothyroacetic Acid Research Articles

Additional considerations in cancer cell radioresistance, integrin αvβ3 and thyroid hormones

ABSTRACT Background The existence of a functional relationship between a certain thyroid hormone analogue and cancer cell radioresistance has been shown by Leith and coworkers. The hormone analogue with relevance to malignant cells’ radioresistance is tetraiodothyroacetic acid (tetrac). Tetrac is the deaminated derivative of L-thyroxine (T4), the principal product of the thyroid gland. Preclinical studies demonstrated that tetrac and chemically modified tetrac (CMT), e.g. a fluorobenzyl-conjugated tetrac analogue, restores radiosensitivity in certain radioresistant tumor cells. Due to their molecular, physico-chemical, and biological properties, actions of CMT analogues are believed to be initiated at the thyroid hormone analogue receptor site on plasma membrane integrin αvβ3. Objective To explore possible molecular mechanisms of the potentially therapeutically beneficial effect of CMT on cancer cells’ sensitivity to radiation, we analyzed actions of CMT analogues on expression of selected sets of genes that have been previously implicated in radioresistance of malignant cells. Discussion and conclusions In the current study, we report that genome-wide gene expression profiling analysis of human glioblastoma (GBM) and acute myelocytic leukemia (AML) cell lines exposed in vitro to noncytotoxic doses of CMT has identified decreased expression of discrete trios of genes each of which was previously linked to cancer cells’ radioresistance. Following the CMT treatment in AML cells, expression of PARP9, PARP15 and STAT3 genes was significantly reduced, while in GBM cells, expression of PRKDC, EGFR and CCNDI was significantly decreased by the drug. Notably, a broader spectrum of genes implicated in cancer cells’ radioresistance was observed in primary patient-derived GBM cells after the CMT treatment. Extensive additional experimental and clinical studies are indicated, including analyses of individual patient tumor genomics and of an array of different tumor types to define the sub-sets of tumors manifesting radioresistance in which tetrac-based agents may be expected to enhance therapeutic effects of radiation.

RETRACTED: Godugu et al. Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma. Cancers 2021, 13, 2780.

The journal retracts the article, "Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma" [...].

Tiratricol, a thyroid hormone metabolite, has potent inhibitory activity against human dihydroorotate dehydrogenase.

Human dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in-house library of old drugs. We found that tiratricol (3,3',5-triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC50 : 0.754 ± 0.126 μM), and its precursor tetrac (3,3',5,5'-tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC50 : 11.960 ± 1.453 μM). Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ0 , which is different from the positive control A771726. ThermoFMN assay, molecular docking and site-directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.

Correction to “Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin αvβ3 Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme”

Correction to “Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol: High Affinity Thyrointegrin α_vβ₃ Antagonist with Potent Anticancer Activities in Glioblastoma Multiforme”

Overlapping Actions of L-Thyroxine (T4) and Steroids in Breast Cancer Cells: Mediation by Cell Surface Integrin αvβ3

The overlap of actions of nonpeptide small endocrine molecules—thyroid hormone and steroids—include two panels of actions. One set is initiated at the nuclear receptors for these hormones and a second set of actions for both hormones is initiated at the extracellular domain of plasma membrane integrin αvβ3. This brief review is concerned with integrin-based receptors on breast cancer cells. On such cells, thyroid hormone as L-thyroxine (T4) at physiological concentrations can stimulate proliferation of breast cancer cells via the thyroid hormone analogue receptor on αvβ3 and, in the absence of estrogen, via the nuclear estrogen receptor-α (ER α). Such observations emphasize the postmenopausal relevance of nuclear estrogen receptor. The deaminated T4 derivative, tetraiodothyroacetic acid (tetrac), blocks T4 actions at the integrin. An androgen receptor on the integrin mediates stimulation of breast cancer cell proliferation by dihydrotestosterone (DHT). T4 controls the activation state of the integrin, a factor that may determine the accessibility of the androgen receptor on αvβ3 to DHT and thus to DHT-driven cell proliferation. An estrogen receptor appears to be present on the integrin, but its functions have not been defined. It is not yet known whether tetrac alters function of the steroid receptors that are adjacent to the T4 binding site on αvβ3. The overlap of T4 and steroid functions in breast cancer cells may offer additional options for clinical management of this type of cancer.

Discovery of novel thyrointegrin αvβ3 antagonist fb-PMT (NP751) in the management of human glioblastoma multiforme.

Thyrointegrin αvβ3 receptors are unique molecular cancer therapeutic targets because of their overexpression on cancer and rapidly dividing blood vessel cells compared and quiescent on normal cells. A macromolecule, TriAzole Tetraiodothyroacetic acid (TAT) conjugated to polyethylene glycol with a lipophilic 4-fluorobenyl group (fb-PMT and NP751), interacts with high affinity (0.21 nM) and specificity with the thyrointegrin αvβ3 receptors on the cell surface without nuclear translocation in contrast to the non-polymer conjugated TAT. The following in vitro assays were carried out to evaluate NP751 including binding affinity to different integrins, transthyretin (TTR)-binding affinity, glioblastoma multiforme (GBM) cell adhesion, proliferation assays, nuclear translocations, chorioallantoic membrane model of angiogenesis, and microarray for molecular mechanisms. Additionally, in vivo studies were carried out to evaluate the anticancer efficacy of NP751, its biodistribution, and brain GBM tumor versus plasma levels kinetics. NP751 demonstrated a broad spectrum of antiangiogenesis and anticancer efficacy in experimental models of angiogenesis and xenografts of human GBM cells. Tumor growth and cancer cells' viability were markedly decreased (by > 90%; P < .001) in fb-PMT-treated U87-luc or 3 different primary human GBM xenograft-bearing mice based on tumor in vivo imaging system (IVIS) imaging and histopathological examination, without relapse upon treatment discontinuation. Additionally, it effectively transports across the blood-brain barrier via its high-affinity binding to plasma TTR with high retention in brain tumors. NP751-induced effects on gene expression support the model of molecular interference at multiple key pathways essential for GBM tumor progression and vascularization. fb-PMT is a potent thyrointegrin αvβ3 antagonist with potential impact on GBM tumor progression.

Pharmacokinetics of fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (NP751), a novel anticancer thyrointegrin αvβ3 antagonist.

We have recently reported on the development of fb-PMT (NP751), a conjugate of the thyroid hormone metabolite tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol 36. It exhibited high affinity for thyrointegrin αvβ3 receptor and potent anti-angiogenic and anticancer activity in vivo. The objective of the current study is to determine the pharmacokinetics (PK) of fb-PMT in experimental animals, such as mice, rats, and monkeys. NP751 was quantified using a propylene diamine-modified tetraiodothyroacetic acid (DAT) as an internal standard. The limit of quantification (LOQ) for fb-PMT was 1.5ng/μL and the recovery efficiency was 93.9% with the developed method. The peak plasma concentration (Cmax) and the area under the curve (AUC) results at different doses in mice, rats and monkeys suggest that pharmacokinetics of NP751 is dose-dependent within the dose ranges administered. Results indicate that NP751 has comparable PK parameters that provides enough exposure as a molecularly tumor targeted molecule in multiple species and is a promising anticancer therapeutic.

Binding Characteristics of Thyroid Hormone Distributor Proteins to Thyroid Hormone Metabolites.

Background: In contrast to the thyroid hormones (THs) 3,3',5-triiodothyronine (T3) and 3,3',5,5'-tetraiodothyronine (thyroxine or T4), the binding characteristics of the thyroid hormone distributor proteins (THDP), thyroxine-binding globulin (TBG), albumin, and transthyretin in relation to TH metabolites are mostly lacking. In this study, we determined the distribution and binding affinity of TH metabolites to THDP, which is important for adequate interpretation of TH metabolite concentrations. Methods: Distribution of 125I-3,3'-diiodothyronine (3,3'-T2), -T3, -3,3',5'-triiodothyronine (rT3), -3,3',5-triiodothyroacetic acid (TA3), and -3,3',5,5'-tetraiodothyroacetic acid (TA4) to TBG, transthyretin, and albumin was determined by agar gel electrophoresis. The rank order of affinity (IC50) of TBG and transthyretin to thyronine (T0), 3-monoiodothyronine (3-T1), 3,5-diiodothyronine (3,5-T2), 3,3'-T2, T3, rT3, T4, TA3, and TA4 was determined with a radioligand, competitive binding assay. In healthy subjects, associations of serum TBG, transthyretin, and albumin with TH and its metabolites were analyzed using multiple linear regression models, adjusted for sex and age. Results: While T3 and T4 are predominantly bound to TBG, we demonstrated that the predominant THDP of 3,3'-T2 and rT3 is albumin, of TA3 is transthyretin and albumin, and of TA4 is transthyretin. With the radioligand binding assay, we showed that the rank order of affinity was T4>TA4 = rT3>T3>TA3 = 3,3'-T2 > 3-T1 = 3,5-T2>T0 for TBG (IC50-range: 0.36 nM to >100 μM) and TA4>T4 = TA3>rT3>T3 > 3,3'-T2 > 3-T1 > 3,5-T2>T0 for transthyretin (IC50-range: 0.94 nM to >100 μM). TBG, transthyretin, and albumin were not associated with T0, 3-T1, 3,3'-T2, rT3, and TA4. Conclusions: Differences in serum TBG, transthyretin, and albumin concentrations within the reference interval do not influence serum concentrations of T0, 3-T1, 3,3'-T2, rT3, and TA4. Distribution of TH metabolites between THDP differs from T4 and T3, which predominantly bind to TBG. The results from our study have potential clinical importance for adequate interpretation of TH metabolism in (patho)physiology.

Effects of Anticancer Agent P-bi-TAT on Gene Expression Link the Integrin Thyroid Hormone Receptor to Expression of Stemness and Energy Metabolism Genes in Cancer Cells.

Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against glioblastoma multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10−6 tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism. Significantly downregulated transcripts included multiple energy-metabolism-related genes: electron transport chain genes ATP5A1 (ATP synthase 1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase (ubiquinone) FA8), NDUFV2I and other NDUF genes. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Qualitatively similar actions of P-bi-TAT on expression of subsets of energy-metabolism-linked genes were also detected in established human GBM and pancreatic cancer cell lines. In conclusion, acting at αvβ3 integrin, P-bi-TAT caused downregulation in human cancer cells of expression of a large number of genes involved in electron transport and oxidative phosphorylation. These observations suggest that cell surface thyroid hormone receptors on αvβ3 regulate expression of genes relevant to tumor cell stemness and energy metabolism.

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin αvβ3 Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.

Thyroid hormone L thyroxine stimulates pancreatic carcinoma cell proliferation via thyrointegrin αvβ3 receptors, and antagonist tetraiodothyroacetic acid (tetrac) inhibits cancer cell growth. Chemically modified bis-triazole-tetrac conjugated with polyethylene glycol (P-bi-TAT) has higher binding affinity to αvβ3 receptors compared to tetrac. We investigated the antiproliferation effect of P-bi-TAT in pancreatic cancer cells (SUIT2) and its radio- and chemo-sensitizing roles in a mouse model of pancreatic cancer. P-bi-TAT treatment increased tumor-targeted radiation-induced cell death and decreased tumor size. P-bi-TAT acted as a chemo-sensitizer and enhanced the 5-fluorouracil (5FU) effect in decreasing pancreatic tumor weight compared to 5FU monotherapy. Withdrawal of treatment continued the tumor regression; however, the 5FU group showed tumor regrowth. The mechanisms of the anti-cancer activity of P-bi-TAT on SUIT2 cells were assessed by microarray experiments, and genome-wide profiling identified significant alterations of 1348 genes’ expression. Both down-regulated and up-regulated transcripts suggest that a molecular interference at the signaling pathway-associated gene expression is the prevalent mode of P-bi-TAT anti-cancer activity. Our data indicate that non-cytotoxic P-bi-TAT is not only an anti-cancer agent but also a radio-sensitizer and chemo-sensitizer that acts on the extracellular domain of the cell surface αvβ3 receptor.

In Vivo Clearance of Apoptotic Debris From Tumor Xenografts Exposed to Chemically Modified Tetrac: Is There a Role for Thyroid Hormone Analogues in Efferocytosis?

Apoptosis is induced in cancer cells and tumor xenografts by the thyroid hormone analogue tetraiodothyroacetic acid (tetrac) or chemically modified forms of tetrac. The effect is initiated at a hormone receptor on the extracellular domain of plasma membrane integrin αvβ3. The tumor response to tetrac includes 80% reduction in size of glioblastoma xenograft in two weeks of treatment, with absence of residual apoptotic cancer cell debris; this is consistent with efferocytosis. The molecular basis for efferocytosis linked to tetrac is incompletely understood, but several factors are proposed to play roles. Tetrac-based anticancer agents are pro-apoptotic by multiple intrinsic and extrinsic pathways and differential effects on specific gene expression, e.g., downregulation of the X-linked inhibitor of apoptosis (XIAP) gene and upregulation of pro-apoptotic chemokine gene, CXCL10. Tetrac also enhances transcription of chemokine CXCR4, which is relevant to macrophage function. Tetrac may locally control the conformation of phagocyte plasma membrane integrin αvβ3; this is a cell surface recognition system for apoptotic debris that contains phagocytosis signals. How tetrac may facilitate the catabolism of the engulfed apoptotic cell debris requires additional investigation.

Heteronemin and tetrac derivatives suppress non-small cell lung cancer growth via ERK1/2 inhibition

The most common cancer, lung cancer, causes deaths worldwide. Most lung cancer patients have non-small cell lung carcinomas (NSCLCs) with a poor prognosis. The chemotherapies frequently cause resistance therefore search for new effective drugs for NSCLC patients is an urgent and essential issue. Deaminated thyroxine, tetraiodothyroacetic acid (tetrac), and its nano-analogue (NDAT) exhibit antiproliferative properties in several types of cancers. On the other hand, the most abundant secondary metabolite in the sponge Hippospongia sp., heteronemin, shows effective cytotoxic activity against different types of cancer cells. In the current study, we investigated the anticancer effects of heteronemin against two NSCLC cell lines, A549 and H1299 cells in vitro. Combined treatment with heteronemin and tetrac derivatives synergistically inhibited cancer cell growth and significantly modulated the ERK1/2 and STAT3 pathways in A549 cells but only ERK1/2 in H1299 cells. The combination treatments induce apoptosis via the caspases pathway in A549 cells but promote cell cycle arrest via CCND1 and PCNA inhibition in H1299 cells. In summary, these results suggest that combined treatment with heteronemin and tetrac derivatives could suppress signal transduction pathways essential for NSCLC cell growth. The synergetic effects can be used potentially as a therapeutic procedure for NSCLC patients.

Targeting Thyrointegrin αvβ3 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia.

BackgroundAcute myeloid leukemia (AML) is associated with poor long-term survival, even with newer therapeutic agents. Here, we show the results of our preclinical study, in which we evaluated the efficacy of a new thyrointegrin αvβ3 antagonist, named fluorobenzyl polyethylene glycol conjugated tetraiodothyroacetic acid (fb-PMT).Methods and Resultsfb-PMT (NP751) is a potent αvβ3 antagonist of molecular weight of 2,478.9 Da. it represents a conjugate of tetraiodothyroacetic acid (tetrac) and monodisperse polyethylene glycol (PEG36), with a 4-fluorobenzyl group capping the other end of the PEG. fb-PMT effectively suppresses the malignant growth of human acute myeloid leukemia (AML) after successful engraftment in transgenic NSG-S xenograft mouse models of either established human AML cell line or primary AML cells. Daily treatment with fb-PMT (1–10 mg/kg body weight) subcutaneously (s.c.) for 3–4 weeks was associated with marked regression of leukemogenesis and extended survival in both models. The efficiency of the fb-PMT therapy was verified using in vivo imaging system (IVIS) imaging, flow cytometry, and histopathological examination to monitor the engraftment of leukemic cells in the bone marrow and other organs. fb-PMT therapy for 3–4 weeks at 3 and 10 mg/kg daily doses exhibited significant reduction (p < 0.0001) of leukemic cell burden of 74% and >95%, respectively. All fb-PMT-treated mice in the 10 mg/kg treatment arm successfully maintained remission after discontinuing the daily treatment. Comprehensive fb-PMT safety assessments demonstrated excellent safety and tolerability at multiple folds above the anticipated human therapeutic doses. Lastly, our genome-wide microarray screens demonstrated that fb-PMT works through the molecular interference mechanism with multiple signaling pathways contributing to growth and survival of leukemic cells.ConclusionOur preclinical findings of the potent anticancer activities of fb-PMT and its favorable safety profiles warrant its clinical investigation for the effective and safe management of AML.

Pharmacokinetics and biodistribution of a novel anticancer thyrointegrin \u03b1v\u03b23 antagonist: triazole modified tetraiodothyroacetic acid conjugated to polyethylene glycol (P-bi-TAT)

We previously developed a triazole modified tetraiodothyroacetic acid (TAT) conjugated to a polyethylene glycol (PEG)-based thyrointegrin αvβ3 antagonist targeted compound, called P-bi-TAT. It exhibited potent anti-angiogenic and anticancer activities in vivo. The objective of the current study is to develop a quantitative bioanalytical method for P-bi-TAT using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to elucidate pharmacokinetics (PK) and biodistribution of P-bi-TAT in animals. We used in-source collision-induced dissociation (CID) for ionization of P-bi-TAT in the positive mode, followed by multiple reaction monitoring (MRM) for quantification. P-bi-TAT was quantified using P-mono-TAT as an internal standard because of its similarity in structure and physicochemical properties to P-bi-TAT. The LOQ for P-bi-TAT was 30 ng/μL and the recovery efficiency was 76% with the developed method. Cmax and AUC results at different doses (1, 3, 10 mg/kg) in rats suggest that P-bi-TAT is dose-dependent within the range administered. Results for Cmax and AUC in monkeys at a low dose (25 mg/kg) were comparable to those in rats. Biodistribution of subcutaneously administered P-bi-TAT in the brain of rats ranged from 7.90 to 88.7 ng/g brain weight, and levels of P-bi-TAT in the brain were dose-dependent. The results suggest that P-bi-TAT is a potential candidate as a molecular-targeted anticancer therapeutic with blood-brain barrier permeability and acceptable PK parameters. Its accumulation in organs, toxicokinetic, and pharmacodynamics needs to be further investigated.Graphical

Novel Polyethylene Glycol-Conjugated Triazole Derivative with High Thyrointegrin αvβ3 Affinity in Acute Myeloid Leukemia Management.

Simple SummaryThe integrin αvβ3 antagonist (P-bi-TAT) is associated with the downregulation of signaling pathways, especially NF-κB pathway, which play an important role in leukemogenesis. Our results provide a rationale for further evaluation of the αvβ3 antagonists as providing potential therapeutic utility not only in AML but also in different malignancies.(1) Background: Acute myeloid leukemia (AML) accounts for up to one-third of more than 60,000 leukemia cases diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is associated with adverse prognosis and resistance to chemotherapies. A novel anticancer compound Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) interacts with high affinity (Ki 0.3 nM) and specificity with the thyrointegrin αvβ3. We evaluated P-bi-TAT activities in two different AML models representing monocytic and myelocytic forms of acute leukemia. (2) Methods and Results: The in vivo AML models were established prior to initiation of treatment protocols by grafting human leukemia cells in immunocompromised mice. IVIS imaging scans revealed that leukemic colonies were extensively established throughout the bone marrow, liver, and lung of the untreated animals. In animals treated with P-bi-TAT at daily doses ranging from 1–10 mg/kg, subcutaneously for 2–3 weeks, IVIS imaging scans revealed 95% reduction in bone marrow colonies and leukemic colonies in liver and lung. Also, the leukemic cells were not detected in bone marrow samples of P-bi-TAT-treated animals. The anti-neoplastic effect of P-bi-TAT administration on leukemic cells was associated with marked inhibition of NF-κB activity. We conclude that experimental P-bi-TAT therapy in vivo appears extraordinarily effective against the two forms of human AML models in mice. Because the P-bi-TAT molecular target, thyrointegrin αvβ3, is consistently expressed in many, if not all, clinical AML samples, P-bi-TAT-based therapy seems to have significant clinical potential in treating most AML sub-types. Hence, P-bi-TAT represents a promising targeted therapeutic agent for AML patients.

Nano-Targeting of Thyrointegrin αvβ3 Receptor in Solid Tumors and Impact on Radiosensitization.

Tetraiodothyroacetic acid is a ligand of thyrointegrin αvβ3, a protein that is highly expressed in various solid tumors and surrounding neovascular regions. Its nano derivative, Nano-diamino-tetrac (NDAT), has anticancer properties in preclinical models, enhances radiosensitivity, and inhibits cancer cell growth in vitro after X-ray irradiation. Using a novel experimental system developed to deliver accurate radiation dose to tumors under sterile conditions, this study establishes NDAT's radiosensitizing effect in SUIT-2 pancreatic cancer and H1299 non-small cell lung carcinoma xenografts in athymic mice for tumor-targeted radiation. In this work, low-melting-point Lipowitz alloy was used to shield normal organs and allow accurate tumor-targeted irradiation. Over a three-week period, mice with SUIT-2 xenografts received daily NDAT treatment at different doses (0, 1, 3, or 10 mg/kg body weight) and tumor-targeted irradiation (1 or 5 Gy). Validation was performed with a test dose of 30 Gy to mice bearing SUIT-2 xenografts and resulted in more than 80% reduction in tumor weight, compared to nonirradiated tumor weight. The results of this work showed that NDAT had a radiosensitizing effect in a dose-dependent manner in decreasing tumor growth and viability. An enhanced anticancer effect of NDAT (1 mg/kg body weight) was observed in mice with H1299 xenografts receiving 5 Gy tumor-targeted irradiation, indicated by decreased tumor weight and increased necrosis, compared to nonirradiated tumors. This technique demonstrated accurate tumor-targeted irradiation with new shielding methodology, and combined with thyrointegrin antagonist NDAT treatment, showed anticancer efficacy in pancreatic cancer and non-small cell lung carcinoma.

Nano-Strategies Targeting the Integrin αvβ3 Network for Cancer Therapy

Integrin αvβ3, a cell surface receptor, participates in signaling transduction pathways in cancer cell proliferation and metastasis. Several ligands bind to integrin αvβ3 to regulate proliferation and metastasis in cancer cells. Crosstalk between the integrin and other signal transduction pathways also plays an important role in modulating cancer proliferation. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) activates the downstream integrin FAK to stimulate biological activities including cancer proliferation and metastasis. Blockage of signals related to integrin αvβ3 was shown to be a promising target for cancer therapies. 3,3′,5,5′-tetraiodothyroacetic acid (tetrac) completely binds to the integrin with the thyroid hormone to suppress cancer proliferation. The (E)-stilbene analog, resveratrol, also binds to integrin αvβ3 to inhibit cancer growth. Recently, nanotechnologies have been used in the biomedical field for detection and therapeutic purposes. In the current review, we show and evaluate the potentiation of the nanomaterial carrier RGD peptide, derivatives of PLGA-tetrac (NDAT), and nanoresveratrol targeting integrin αvβ3 in cancer therapies.

Actions of Thyroid Hormones on Thyroid Cancers.

L-Thyroxine (T4) is the principal ligand of the thyroid hormone analogue receptor on the extracellular domain of integrin αvβ3. The integrin is overexpressed and activated in cancer cells, rapidly dividing endothelial cells, and platelets. The biologic result is that T4 at physiological concentration and without conversion to 3,3’,5-triiodo-L-thyronine (T3) may stimulate cancer cell proliferation and cancer-relevant angiogenesis and platelet coagulation. Pro-thrombotic activity of T4 on platelets is postulated to support cancer-linked blood clotting and to contribute to tumor cell metastasis. We examine some of these findings as they may relate to cancers of the thyroid. Differentiated thyroid cancer cells respond to physiological levels of T4 with increased proliferation. Thus, the possibility exists that in patients with differentiated thyroid carcinomas in whom T4 administration and consequent endogenous thyrotropin suppression have failed to arrest the disease, T4 treatment may be stimulating tumor cell proliferation. In vitro studies have shown that tetraiodothyroacetic acid (tetrac), a derivative of T4, acts via the integrin to block T4 support of thyroid cancer and other solid tumor cells. Actions of T4 and tetrac or chemically modified tetrac modulate gene expression in thyroid cancer cells. T4 induces radioresistance via induction of a conformational change in the integrin in various cancer cells, although not yet established in thyroid cancer cells. The thyroid hormone receptor on integrin αvβ3 mediates a number of actions of T4 on differentiated thyroid cancer cells that support the biology of the cancer. Additional studies are required to determine whether T4 acts on thyroid cancer cells.

Discovery of dual targeting PEGylated BG-P1600-TAT to norepinephrine transporter (NET) and thyrointegrin αvβ3 in the treatment of neuroblastoma

Polymer-drug conjugates are growing in interest as novel anticancer agents for targeted cancer therapy. The aim of this study was to synthesize a poly(ethylene glycol) (PEG) conjugated anticancer drug for neuroblastoma, which is the most common extracranial solid tumor of childhood and the deadliest tumor of infancy. In our previous studies, we designed and synthesized a dual targeting agent using benzylguanidine (BG) conjugated with the high affinity thyrointegrin αvβ3 antagonist TriAzole Tetraiodothyroacetic acid (TAT) via non-cleavable bonding to PEG400 to make BG-P400-TAT and its derivatives as agents against neuroblastoma. Here, we improved the pharmacodynamic properties and increased the solubility by changing the polymer length to 1600 molecular weight. The TAT group, which acts as an integrin αvβ3 antagonist, and the BG group, which can be taken up by neuroblastoma cells through the norepinephrine transporter (NET) system, are conjugated to PEG1600 to make BG-PEG1600-TAT. The binding affinity of BG-PEG1600-TAT was 40-fold higher to integrin αvβ3 versus BG-P400-TAT and was associated with greater anticancer activities against neuroblastoma cells (SK-N-F1 and SKNAS) implanted in SCID mice along with broad spectrum anti-angiogenesis activities versus the FDA approved anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody Avastin (bevacizumab). In conclusion, our novel dual targeting of NET and αvβ3 receptor antagonist, BG-P1600-TAT demonstrated broad spectrum anti-angiogenesis and anti-cancer activities in suppressing neuroblastoma tumor progression and metastasis. Thus, BG-PEG1600-TAT represents a potential clinical candidate for targeted therapy in neuroblastoma management.

Anti-Cancer Activities of Thyrointegrin αvβ3 Antagonist Mono- and Bis-Triazole Tetraiodothyroacetic Acid Conjugated via Polyethylene Glycols in Glioblastoma.

Simple SummaryDifferent Triazole Tetrac (TAT) thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. TAT containing molecules bind with high affinity to the integrin αvβ3 and plasma protein Transthyretin (TTR), which facilitate transport across the blood brain barrier. Biological studies showed that decreasing the PEG linker size (1600 versus 4000) or having mono-TAT versus bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, and overall anti-cancer efficacy.Integrin αvβ3 receptors are overexpressed in different tumors and their associated neovascularization and hence, represent a potential cancer target. We previously synthesized a high affinity thyrointegrin αvβ3, P4000-bi-TAT (tetrac derivative), with potent anticancer properties. However, the long polydisperse PEG conjugate showed large scaleup and analytical/bioanalytical issues. Hence, in the present study, we synthesized a mono versus bi-triazole tetrac with discrete monodisperse PEG, which provided improvement in scaleup and bioanalysis. In the present study, we compared binding affinity and anticancer activates with a smaller PEG size (P1600-bi-TAT, Compound 2) and the removal of one TAT molecule (P1600-m-TAT, Compound 3) versus P4000-bi-TAT, Compound 1. The results of the selectivity and affinity of TATs showed greater affinity to integrin αvβ3. The xenograft weights and tumor cell viabilities were decreased by >90% at all doses compared to the control (ON Treatment, *** p < 0.001) in cells treated with Compounds 1, 2, and 3 in U87-Luc-treated mice. The in vivo luminescent signals of U87-luc cells reflect the proliferation and distribution of tumor cells in the animals and the maximum intensity corresponding to the maximum tumor cells that the animals could tolerate. We found that the three thyrointegrin αvβ3 antagonists exhibited optimal therapeutic efficacy against U87 or primary glioblastoma cells. Biological studies showed that decreasing the PEG linker size (1600 vs. 4000) or having mono-TAT or bi-TAT had no significant impact on their αvβ3 binding affinity, anti-angiogenesis, or overall anti-cancer efficacy.