Efficacy of a Novel Second-Generation Somatostatin-Dopamine Chimera (TBR-065) in Human Medullary Thyroid Cancer: A Preclinical Study.
Neuroendocrinology
; 111(10): 937-950, 2021.
Article
em En
| MEDLINE
| ID: mdl-33075795
ABSTRACT
INTRODUCTION:
Somatostatin and dopamine (DA) receptors have a pivotal role in controlling hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the anti-tumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-DA chimera, in 2 human MTC cell lines.METHODS:
The effects of lanreotide (LAN) and TBR-065 on cell growth and proliferation, calcitonin (CT) secretion, cell cycle, apoptosis, cell migration, and tumor-induced angiogenesis have been evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA flow cytometry with propidium iodide (PI), Annexin V-FITC/PI staining, electrochemiluminescence immuno assay, wound-healing assay, and zebrafish platform, respectively.RESULTS:
TBR-065 exerted a more prominent anti-tumor activity than LAN in both MTC cell lines, as shown by inhibition of cell proliferation (maximal inhibition in TT -50.3 and -37.6%, respectively; in MZ-CRC-1 -58.8 and -27%, respectively) and migration (in TT -42.7 and -22.9%, respectively; in MZ-CRC-1 -75.5 and -58.2%, respectively). Only the new chimera decreased significantly the fraction of cells in S phase (TT -33.8%; MZ-CRC-1 -18.8%) and increased cells in G2/M phase (TT +13%; MZ-CRC-1 +30.5%). In addition, TBR-065 exerted a more prominent pro-apoptotic effect than LAN in TT cells. A concomitant decrease in CT secretion was observed after 2 days of incubation with both drugs, with a more relevant effect of TBR-065. However, neither LAN nor TBR-065 showed any effect on tumor-induced angiogenesis, as evaluated using a zebrafish/tumor xenograft model. DISCUSSION/CONCLUSION:
In MTC cell lines, a second-generation somatostatin-DA analog, TBR-065, exerts a more relevant anti-tumor activity than LAN, through modulation of cell cycle, induction of apoptosis, and reduction in migration. Further studies are required to establish whether TBR-065 has comparable potent inhibitory effects on tumor growth in vivo.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Somatostatina
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Neoplasias da Glândula Tireoide
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Dopamina
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Carcinoma Neuroendócrino
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Antineoplásicos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article