TY - JOUR
T1 - The induction of myeloma cell death and DNA damage by tetrac, a thyroid hormone derivative
AU - Cohen, Keren
AU - Abadi, Uri
AU - Hercbergs, Aleck
AU - Davis, Paul J.
AU - Ellis, Martin
AU - Ashur-Fabian, Osnat
N1 - Publisher Copyright:
© 2018 Society for Endocrinology.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Integrin
KW - Myeloma
KW - Thyroid hormone derivatives
UR - http://www.scopus.com/inward/record.url?scp=85042544320&partnerID=8YFLogxK
U2 - 10.1530/ERC-17-0246
DO - 10.1530/ERC-17-0246
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C2 - 29018054
AN - SCOPUS:85042544320
SN - 1351-0088
VL - 25
SP - 21
EP - 34
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
IS - 1
ER -