The induction of myeloma cell death and DNA damage by tetrac, a thyroid hormone derivative
- Keren Cohen1,2,3,
- Uri Abadi1,3,
- Aleck Hercbergs4,
- Paul J Davis5,
- Martin Ellis1,3 and
- Osnat Ashur-Fabian1,2,3⇑
- 1Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
- 2Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel
- 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- 4Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA
- 5Department of Medicine, Albany Medical College, Albany, New York, USA
- Correspondence should be addressed to O Ashur-Fabian: osnataf{at}gmail.com
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.
- Received 2 October 2017
- Accepted 10 October 2017
- Made available online as an Accepted Preprint 10 October 2017
- © 2018 Society for Endocrinology