Additional considerations in cancer cell radioresistance, integrin αvβ3 and thyroid hormones

The existence of a functional relationship between a certain thyroid hormone analogue and cancer cell radioresistance has been shown by Leith and coworkers. The hormone analogue with relevance to malignant cells' radioresistance is tetraiodothyroacetic acid (tetrac). Tetrac is the deaminated derivative of L-thyroxine (T4), the principal product of the thyroid gland. Preclinical studies demonstrated that tetrac and chemically modified tetrac (CMT), e.g. a fluorobenzyl-conjugated tetrac analogue, restores radiosensitivity in certain radioresistant tumor cells. Due to their molecular, physico-chemical, and biological properties, actions of CMT analogues are believed to be initiated at the thyroid hormone analogue receptor site on plasma membrane integrin αvβ3.

To explore possible molecular mechanisms of the potentially therapeutically beneficial effect of CMT on cancer cells' sensitivity to radiation, we analyzed actions of CMT analogues on expression of selected sets of genes that have been previously implicated in radioresistance of malignant cells.

In the current study, we report that genome-wide gene expression profiling analysis of human glioblastoma (GBM) and acute myelocytic leukemia (AML) cell lines exposed in vitro to noncytotoxic doses of CMT has identified decreased expression of discrete trios of genes each of which was previously linked to cancer cells' radioresistance. Following the CMT treatment in AML cells, expression of PARP9, PARP15 and STAT3 genes was significantly reduced, while in GBM cells, expression of PRKDC, EGFR and CCNDI was significantly decreased by the drug. Notably, a broader spectrum of genes implicated in cancer cells' radioresistance was observed in primary patient-derived GBM cells after the CMT treatment. Extensive additional experimental and clinical studies are indicated, including analyses of individual patient tumor genomics and of an array of different tumor types to define the sub-sets of tumors manifesting radioresistance in which tetrac-based agents may be expected to enhance therapeutic effects of radiation.