Abstract
Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.
Highlights
Tetraiodothyroacetic acid is a deaminated thyroid hormone analogue that binds to the integrin avb3 receptor for thyroid hormone [1,2]
At first tetrac induced anti-proliferation of cancer cells was studied in the non-perfusion system
Tetrac caused a concentration-dependent reduction in U87MG cell proliferation (Fig. 3A), where 1029 M was least effective, and 1028 and 1027 M caused 15% and 28% decreases in cell counts compared to untreated cells after treatment for 7 d (Fig. 3A)
Summary
Tetraiodothyroacetic acid (tetrac) is a deaminated thyroid hormone analogue that binds to the integrin avb receptor for thyroid hormone [1,2]. Acting at the surface of cancer cells, tetrac alters expression of differentiallyregulated cancer cell survival pathway-relevant genes. These include upregulation of expression of pro-apoptotic BcL-x short form [3] and other pro-apoptotic genes [8], upregulation of anti-angiogenic thrombospondin 1 and downregulation of several families of antiapoptotic genes [8,9]. Bound to the exterior of a nanoparticle, tetrac does not gain access to the cell interior—where it may have thyromimetic activity [10]—and has biological activity at the integrin receptor similar to that of unmodified tetrac, but with desirable effects on cell survival pathway genes that differ from the parent thyroid hormone analogue [8,9]
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