Dual Targeting of Norepinephrine Transporter (NET) Function and Thyrointegrin αvβ3 Receptors in the Treatment of Neuroblastoma

Abstract

Therapeutic targeting of the norepinephrine transporter (NET) function with benzylguanidine (BG), conjugated with the high-affinity thyrointegrin αvβ3 antagonist triazole tetraiodothyroacetic acid, TAT, via noncleavable bonding to poly(ethylene glycol) (PEG 400 ) (P) might allow for effective treatment options in neuroblastoma. BG-P-TAT is a dual-targeting agent, targeting the NET function and the thyrointegrin αvβ3 receptors that are overexpressed in neuroblastoma and other neuroendocrine tumors. Various cancer cells and actively dividing tumor-endothelial cells express the thyrointegrin αvβ3 receptors. In this work, the novel compound BG-P-TAT was synthesized and evaluated in the neuroblastoma SK-N-FI cell line for improved targeting and to offer a new strategy for patients with neuroblastoma. BG-P-TAT demonstrated significant suppression of neuroblastoma tumor progression, growth, and viability in a dose-dependent manner. In conclusion, BG-P-TAT represents a potential lead candidate for the treatment of neuroblastoma and other neuroendocrine tumors.

Anticancer Efficacy and Mechanisms of a Dual Targeting of Norepinephrine Transporter and Thyrointegrin αvβ3 Antagonist in Neuroblastoma

“…Elevated expression of integrin αvβ3 is associated with tumor aggressiveness and is known to confer treatment resistance in neuroblastoma 31 . We have previously shown the synthesis and scaleup of BG-P 400 -TAT and assessed its anti-cancer activity active against in SCID mice xenografted with SK-N-FI cells 13 . Here, we investigated the targetability and anti-tumor activity of BG-P 400 -TAT in SCID and NSG mice with subcutaneous neuroblastoma xenografts using a three neuroblastoma cells.…”

“…The addition of BG maximally concentrated the thyrointegrin αvβ3 antagonist in neuroblastoma. A function of the PEG400 linker is to restrict the molecule to the cell surface and prevent nuclear translocation 13 .…”

“…Benzylguanidine-PEG-TAT (BG-P 400 -TAT) was synthesized at the Pharmaceutical Research Institute 13 . Iscove's Modified Dulbecco's medium (IMDM), fetal bovine serum (FBS), penicillin, streptomycin, and trypsin/EDTA were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

“…Our previous studies reported that a deaminated analog of thyroid hormone, tetraiodothyroacetic acid (tetrac), can block signal transduction mechanisms and mediate the promotion of cancer cell proliferation 11 , 12 . A dual targeting novel ligand, BG-P 400 -TAT and derivatives, where P is polyethylene glycol and TAT is triazole tetraiodothyroacetic acid , can bind to integrin αvβ3, and benzylguanidine (BG) targets NET receptors on neuroblastoma cells 13 , 14 .…”

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

“…Previous studies indicate that integrins are playing a key role in promoting tumor cell survival and invasion, suggesting that therapeutic targeting of the functions of some integrins, such as αvβ3, which has thyroid hormone analogue receptors and it referred to here as thyrointegrin, may suppress the activity of the most aggressive and metastatic cancer cells in AML, breast, and pancreatic malignancies [5][6][7]. Recent studies from our laboratories documented the key role of thyrointegrin αvβ3 in the immune modulation and other crucial biological features of various types of human cancers [8,9].…”