Journal
BIOMEDICINES
Volume 10, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines10040795
Keywords
pancreatic cancer; radiation; chemotherapy; radiation resistance; chemo-resistance; angiogenesis; tumor relapse; thyrointegrin alpha(v)beta(3) antagonist
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Funding
- NanoPharmaceuticals LLC, Rensselaer, NY
- Pharmaceutical Research Institute (PRI) at Albany College of Pharmacy and Health Sciences
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Thyroid hormone L thyroxine stimulates pancreatic carcinoma cell proliferation via thyrointegrin alpha v beta 3 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 alpha v beta 3 receptors compared to tetrac. P-bi-TAT treatment increases tumor-targeted radiation-induced cell death and acts as a chemo-sensitizer, enhancing the effect of 5-fluorouracil (5FU) in pancreatic cancer cells.
Thyroid hormone L thyroxine stimulates pancreatic carcinoma cell proliferation via thyrointegrin alpha v beta 3 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 alpha v beta 3 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 alpha v beta 3 receptor.
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