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The induction of myeloma cell death and DNA damage by tetrac, a thyroid hormone derivative.

The induction of myeloma cell death and DNA damage by tetrac, a thyroid hormone derivative.
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Cohen K, Abadi U, Hercbergs A, Davis PJ, Ellis M, Ashur-Fabian O,


Cohen K, Abadi U, Hercbergs A, Davis PJ, Ellis M, Ashur-Fabian O, (click to view)

Cohen K, Abadi U, Hercbergs A, Davis PJ, Ellis M, Ashur-Fabian O,

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Endocrine-related cancer 2017 10 1025(1) 21-34 doi 10.1530/ERC-17-0246

Abstract

Multiple myeloma (MM) is a plasma cell malignancy in which involvement of the thyroid hormone-integrin αvβ3 pathway was shown, and pharmacologic inhibition of this pathway is a rational approach to disease management. A thyroid hormone derivative, tetraiodothyroacetic acid (tetrac), which inhibits l-thyroxine (T4) and 3,5,3′-triiodo-l-thyronine (T3) binding to αvβ3 integrin, was studied in five MM cell lines and primary bone marrow (BM) MM cells. Tetrac inhibited MM cell proliferation (absolute cell number/viability) and induced caspase-dependent apoptosis (annexin-V/PI and cell cycle). Activation of caspase-9 and caspase-3 was further demonstrated. Moreover, DNA damage markers, ataxia-telangiectasia-mutated (ATM) kinase, poly ADP-ribose polymerase (PARP-1) and histone γH2AX were induced by tetrac. The various tetrac-initiated effects were attenuated by Arg-Gly-Asp (RGD) peptide, suggesting integrin involvement. Primary BM mononuclear cells were harvested from MM patients (n = 39) at various disease stages. Tetrac-induced apoptosis (12/17 samples) and sensitized the cytotoxic action of bortezomib (6/9 samples). Lastly, expression of plasma membrane integrin αvβ3 was shown not only in the malignant plasma clone, but also in other cell populations within the BM samples (n = 25). Tetrac is anti-proliferative and pro-apoptotic in MM and cells may offer a therapeutic approach for this disease.

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