Efficacy of a Novel Second-Generation Somatostatin-Dopamine Chimera (TBR-065) in Human Medullary Thyroid Cancer: A Preclinical Study.

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.

• Authors: Alessandra Dicitore, Maria Celeste Cantone, Germano Gaudenzi, Davide Saronni, Silvia Carra, Maria Orietta Borghi, Manuela Albertelli, Diego Ferone, Leo J Hofland, Luca Persani, Giovanni Vitale
• Journal: Neuroendocrinology (Neuroendocrinology) Vol. 111 Issue 10 Pg. 937-950 ( 2021) ISSN: 1423-0194 [Electronic] Switzerland
• PMID: 33075795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 S. Karger AG, Basel.

Chemical References

• Antineoplastic Agents
• Somatostatin
• Dopamine

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Neuroendocrine (drug therapy)
• Cell Line, Tumor
• Dopamine (analysis)
• Humans
• Somatostatin (analysis)
• Thyroid Neoplasms (drug therapy)