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

Keren Cohen, Uri Abadi, Aleck Hercbergs, Paul J. Davis, Martin Ellis, Osnat Ashur-Fabian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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-lthyronine (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.

Original languageEnglish
Pages (from-to)21-34
Number of pages14
JournalEndocrine-Related Cancer
Volume25
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • Integrin
  • Myeloma
  • Thyroid hormone derivatives

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