Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts

Mousa, Shaker A.; Yalçın, Murat; Bharali, Dhruba J.; Meng, Ran; Tang, Heng Yuan; Lin, Hung Yun; Davis, Faith B.; Davis, Paul J.

doi:10.1016/j.lungcan.2011.10.003

Cited by 76 publications

(48 citation statements)

References 42 publications

(73 reference statements)

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“…This tetrac formulation (NDAT, Nanotetrac) is an effective anticancer agent in vitro and in xenografts. 29,[34][35][36][37] The reformulation has a panel of antitumor and antiangiogenic actions beyond what might be expected simply from the inhibition of the binding of T 4 and T 3 by the integrin. 31,32 The tissue distribution of the integrin encouraged the development of a second function for NDAT -with its attendant large PLGA nanoparticle -namely, as a delivery moiety for existing generic cancer chemotherapeutic agents to tumors and their supporting vasculature.…”

Section: Discussionmentioning

confidence: 99%

Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

Sudha

Bharali

Yalçın

et al. 2017

IJN

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The tetraiodothyroacetic acid (tetrac) component of nano-diamino-tetrac (NDAT) is chemically bonded via a linker to a poly(lactic- co -glycolic acid) nanoparticle that can encapsulate anticancer drugs. Tetrac targets the plasma membrane of cancer cells at a receptor on the extracellular domain of integrin αvβ3. In this study, we evaluate the efficiency of NDAT delivery of paclitaxel and doxorubicin to, respectively, pancreatic and breast cancer orthotopic nude mouse xenografts. Intra-tumoral drug concentrations were 5-fold (paclitaxel; P <0.001) and 2.3-fold (doxorubicin; P <0.01) higher than with conventional systemic drug administration. Tumor volume reductions reflected enhanced xenograft drug uptake. Cell viability was estimated by bioluminescent signaling in pancreatic tumors and confirmed an increased paclitaxel effect with drug delivery by NDAT. NDAT delivery of chemotherapy increases drug delivery to cancers and increases drug efficacy.

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Section: Discussionmentioning

confidence: 99%

Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

Sudha

Bharali

Yalçın

et al. 2017

IJN

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“…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). Yet, these inhibitors were never examined in ovarian cancer models.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvβ3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

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“…We subsequently showed in a variety of xenografts that a formulation of tetrac covalently linked to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT)—an agent thus restricted to the extracellular space and to action at the integrin—effectively slowed tumor growth and reduced vascularity [17–21]. The nanoparticle in this agent is biodegradable poly (lactic-co-glycolic acid) (PLGA).…”

Section: Introductionmentioning

confidence: 99%

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

et al. 2017

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Thyroid hormone as L-thyroxine (T4) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T4 on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T4 action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.Electronic supplementary materialThe online version of this article (doi:10.1007/s12672-017-0293-6) contains supplementary material, which is available to authorized users.

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Tetraiodothyroacetic acid and its nanoformulation inhibit thyroid hormone stimulation of non-small cell lung cancer cells in vitro and its growth in xenografts

Cited by 76 publications

References 42 publications

Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

Targeted delivery of paclitaxel and doxorubicin to cancer xenografts via the nanoparticle of nano-diamino-tetrac

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

Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

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