Novel function of the thyroid hormone analog tetraiodothyroacetic acid: a cancer chemosensitizing and anti-cancer agent

Abstract

Previous studies from our laboratory have demonstrated that thyroid hormones play a key role in cancer progression. In addition, a deaminated form, tetraiodothyroacetic acid (tetrac), that antagonizes the proliferative action of these hormones was found to possess anti-cancer functions through its ability to inhibit cellular proliferation and angiogenesis. The present study was undertaken to investigate whether tetrac could also suppress the development of drug resistance, known as a causative factor of disease relapse. Tetrac was shown to enhance cellular response in vitro to doxorubicin, etoposide, cisplatin, and trichostatin A in resistant tumor cell lines derived from neuroblastoma, osteosarcoma, and breast cancer. The mechanism of action of tetrac did not involve expression of classical drug resistance genes. However, radiolabeled doxorubicin uptake in cells was enhanced by tetrac, suggesting that one or more export mechanisms for chemotherapeutic agents are inhibited. Tetrac was also found to enhance cellular susceptibility to senescence and apoptosis, suggesting that the agent may target multiple drug resistance mechanisms. Tetrac has previously been shown to inhibit tumor cell proliferation in vitro. In vivo studies reported here revealed that tetrac in a pulsed-dose regimen was effective in suppressing the growth of a doxorubicin-resistant human breast tumor in the nude mouse. In this paradigm, doxorubicin-sensitivity was not restored, indicating that (1) the in vitro restoration of drug sensitivity by tetrac may not correlate with in vivo resistance phenomena and (2) tetrac is an effective chemotherapeutic agent in doxorubicin-resistant cells.

Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression

“…Rebbaa et al (2008) have shown that tetrac increases the intracellular residence time of doxorubicin in chemoresistant human breast MCF-7 cells, thus restoring chemosensitivity to this agent. Because efflux pumps-e.g., P-glycoprotein (P-gp) and other multidrug resistance proteins (MRPs) (Sharom, 2011) are the basis of resistance in tumor cells to certain anti-cancer agents, it was proposed that such pump activity was in fact opposed by tetrac.…”

“…These other agents include etoposide, cisplatin and trichostatin A (Rebbaa et al, 2008), however, and all three relate in one way or another to P-gp. Tetrac also appears to sensitize cancer cells to cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR) and the antibody of course does not depend upon intracellular retention for its effect.…”

“…A thyroid hormone on plasma membrane integrin v3 initiates the actions of the hormone and certain analogues on angiogenesis Davis et al, 2009), on tumor cell proliferation (Rebbaa, 2008;Yalcin, Bharali et al, 2010;Yalcin et al, 2010;Meng et al, 2011) and on cancer cell radiosensitivity Hercbergs et al, 2011). These effects are initiated nongenomically, i.e., are independent of the classical nuclear receptor for thyroid hormone (TR) (Cheng et al, 2010), and may have downstream intracellular consequences that involve specific protein trafficking (Cao et al, 2009) and modulation of expression of specific genes involved in cancer cell survival pathways.…”

“…Covalently bound to a biodegradable nanoparticle that is unable to access the interior of the cell, a thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), acts exclusively at a receptor site on integrin v3 to block actions of L-thyroxine (T 4 ) and 3, 5, 3'-triiodo-L-thyronine (T 3 ) on new blood vessel formation and cancer cell division ; However, nanoparticulate tetrac (nanotetrac) and, to a lesser extent, unmodified tetrac have a panel of cancer-relevant actions in the absence of T 4 and T 3 Davis et al, 2011). These actions include modulation of tumor cell chemosensitivity (Rebbaa, A., et al, 2008), disordering of crosstalk between the integrin and nearby receptors for vascular endothelial growth factor (VEGF) Luidens et al, 2010) and epidermal growth factor (EGF) (Lin et al, 1999;Shih et al, 2004), and antagonism of components of the inflammatory process that may be important to cancer cell biology. This review is focused on these lesser known actions of thyroid hormone analogues at integrin v3 beyond effects on cancer cell proliferation/apoptosis and angiogenesis.…”

Radiosensitization and production of DNA double-strand breaks in U87MG brain tumor cells induced by tetraiodothyroacetic acid (tetrac)

“…[16][17][18] Because of the range of effects of tetrac on tumor cellsincluding, as mentioned above, decreased cell proliferation, anti-angiogenesis, defeat of tumor cell survival pathways and increased intracellular residence time of a conventional cancer chemotherapeutic agent 19 -we asked if tetrac could affect killing of tumor cells by ionizing radiation. A previous study we conducted showed that tetrac indeed sensitized GL261 cells in vitro to 250 kVp x-irradiation.…”