Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin αvβ3 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.