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Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin α_vβ₃ Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.

ABSTRACT: 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.

SUBMITTER: Sudha T

PROVIDER: S-EPMC9032383 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin α<sub>v</sub>β<sub>3</sub> Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.

Sudha Thangirala T Godugu Kavitha K Glinsky Gennadi V GV Mousa Shaker A SA

Biomedicines 20220329 4

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 ...[more]

PMID: 35453545

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Project description: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.

Dataset Information

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin α_vβ₃ Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.

Publications

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin α<sub>v</sub>β<sub>3</sub> Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.

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Dataset Information

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

Publications

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin α<sub>v</sub>β<sub>3</sub> Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin α_vβ₃ Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer.