Efficacy of a novel second-generation somatostatin-dopamine chimera (TBR-065) in human medullary thyroid cancer: a preclinical study

2020 ◽  
Author(s):  
Alessandra Dicitore ◽  
Maria Celeste Cantone ◽  
Germano Gaudenzi ◽  
Davide Saronni ◽  
Silvia Carra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Second Generation ◽  
Medullary Thyroid Cancer ◽  
Preclinical Study ◽  
Medullary Thyroid ◽  
Calcitonin Secretion

Introduction: Somatostatin and dopamine receptors have a pivotal role in control of hormone secretion and cell proliferation in different neuroendocrine neoplasms, including medullary thyroid cancer (MTC). In the present preclinical study, we evaluated the antitumor activity of TBR-065 (formerly BIM-23B065), a second-generation somatostatin-dopamine chimera, in two human MTC cell lines. Methods: the effects of lanreotide (LAN) and TBR-065 on the cell growth proliferation, calcitonin secretion, cell cycle, apoptosis, cell migration and tumor-induced angiogenesis have been evaluated through MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ECLIA assay, wound-healing assay and zebrafish platform, respectively. Results: TBR-065 exerted a more prominent antitumor activity compared to 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 compared to LAN in TT cells. A concomitant decrease of calcitonin 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-dopamine analogue, TBR-065, exerts a more relevant anti-tumor activity, as compared with 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.

scholarly journals RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 860
Author(s):  
Chia-Herng Yue ◽  
Muhammet Oner ◽  
Chih-Yuan Chiu ◽  
Mei-Chih Chen ◽  
Chieh-Lin Teng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Medullary Thyroid Cancer ◽  
Receptor Protein ◽  
Cancer Cell Proliferation ◽  
Thyroid Cancer Cell ◽  
Cancer Proliferation ◽  
Medullary Thyroid

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.

Effects of Boric Acid on Invasion, Migration, Proliferation, Apoptosis, Cell Cycle and miRNAs in Medullary Thyroid Cancer Cells

2021 ◽  
Author(s):  
Onurcan Yıldırım ◽  
Mücahit Seçme ◽  
Yavuz Dodurga ◽  
Gülçin Abban Mete ◽  
Semin Melahat Fenkci
Keyword(s):  
Cell Cycle ◽  
Wound Healing ◽  
Thyroid Cancer ◽  
Comet Assay ◽  
Boric Acid ◽  
Colony Formation ◽  
Dose Group ◽  
Medullary Thyroid Cancer ◽  
Wound Healing Assay ◽  
Medullary Thyroid

Abstract Background: Medullary thyroid cancer (MTC), which makes up 5-10% of all thyroid cancers, is a highly aggressive and chemotherapeutically resistant cancer originating from parafollicular C cells of the thyroid. In recent years, testing of new biological, chemical or natural compounds as an alternative to existing agents used in cancer treatment has been a popular research topic. One of these compounds is boric acid originating from the element boron, and studies have shown that it has anti-carcinogenic, anti-osteoporotic and anti-oxidant effects. Purpose: The aim of this study is to determine the therapeutic effects of boric acid on cell proliferation, invasion, migration, colony formation, cell cycle and apoptosis mechanisms in TT medullary thyroid cancer cell line under in vitro conditions.Methodology: The effects of boric acid on cell viability was determined by XTT assay. Total RNA was isolated by Trizol reagent. Gene and miRNA expressions were analyzed by RT-PCR. Effects of boric acid on apoptosis were analyzed by TUNEL assay and genotoxicity was performed by comet assay. Effects of boric acid on cell invasion, colony formation and cell migration were detected by matrigel-chamber, colony formation assay and wound healing assay, respectively. Results: In order to determine the effect of boric acid on cell viability and 50% lethal dose, the XTT method was employed and IC50 dose was found to be 35 μM at 48th hour. A real-time PCR test was used to investigate changes in cell cycle and apoptosis related genes and proteins and identified miRNAs under the addition of boric acid. In addition, miR-21 was significantly reduced in medullary thyroid cancer associated with cancer aggressiveness and poor prognosis. Using the Tunnel test, the apoptosis rate in the dose group cells were found as 14%. Matrigel invasion test showed a 30.8% decrease in invasion in the dose group and colony formation test decreased 67.9% in the dose group. Using the wound healing assay, it has been found that migration was reduced, and the Comet assay has shown that DNA fractures increased after treatment with boric acid.Conclusion: In conclusion, the findings of this study have shown that boric acid can be used as a potential anticancer agent in medullary thyroid cancer and other cancers caused by similar mechanisms.

scholarly journals MOF Regulates TNK2 Transcription Expression to Promote Cell Proliferation in Thyroid Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Danyang Li ◽  
Yang Yang ◽  
Bo Chen ◽  
Xinghong Guo ◽  
Shuang Gao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cell Lines ◽  
Histone Acetyltransferase ◽  
Expression Level ◽  
Cancer Tissue ◽  
Histone H4 ◽  
Tissue Samples ◽  
Promote Cell Proliferation

MOF is a well-known histone acetyltransferase to catalyze acetylation of histone H4 lysine 16 (K16), and it is relevant to diverse biological processes, such as gene transcription, cell cycle, early embryonic development and tumorigenesis. Here, we identify MOF as an oncogene in most thyroid cancer. It is found that expression level of MOF was significantly upregulated in most thyroid cancer tissue samples and cell lines. MOF-deficient in both BHP-10-3 and TT2609 cell lines inhibited cell proliferation by blocking the cell cycle in G1 phase and enhanced cell apoptosis. Mechanistically, MOF bound the TNK2 promoter to activate TNK2 transcription. Furthermore, the expression level of TNK2 was decreased with the histone acetyltransferase inhibitor. Besides, MOF promoted proliferation of thyroid cancer cells through increased phosphorylation of AKT, thus activating the PI3K/AKT pathway. Ultimately, our findings indicated that MOF played an oncogene role in development and progression of thyroid cancer and may be a potential novel target for the treatment of thyroid cancer.

Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells

2012 ◽  
Vol 19 (3) ◽  
pp. 447-456 ◽  
Author(s):  
Joanna Klubo-Gwiezdzinska ◽  
Kirk Jensen ◽  
John Costello ◽  
Aneeta Patel ◽  
Victoria Hoperia ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Cell Lines ◽  
Medullary Thyroid Cancer ◽  
Molecular Targets ◽  
Inhibitory Effects ◽  
Medullary Thyroid ◽  
Growth Inhibitory ◽  
Tt Cells

Medullary thyroid cancer (MTC) is associated with activation of mammalian target of rapamycin (mTOR) signaling pathways. Recent studies showed that the antidiabetic agent metformin decreases proliferation of cancer cells through 5′-AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR. In the current study, we assessed the effect of metformin on MTC cells. For this purpose, we determined growth, viability, migration, and resistance to anoikis assays using two MTC-derived cell lines (TT and MZ-CRC-1). Expressions of molecular targets of metformin were examined in MTC cell lines and in 14 human MTC tissue samples. We found that metformin inhibited growth and decreased expression of cyclin D1 in MTC cells. Treatment with metformin was associated with inhibition of mTOR/p70S6K/pS6 signaling and downregulation of pERK in both TT and MZ-CRC-1 cells. Metformin had no significant effects on pAKT in the cell lines examined. Metformin-inducible AMPK activation was noted only in TT cells. Treatment with AMPK inhibitor (compound C) or AMPK silencing did not prevent growth inhibitory effects of metformin in TT cells. Metformin had no effect on MTC cell migration but reduced the ability of cells to form multicellular spheroids in nonadherent conditions. Immunostaining of human MTC showed over-expression of cyclin D1 in all tumors compared with corresponding normal tissue. Activation of mTOR/p70S6K was detected in 8/14 (57.1%) examined tumors. Together, these findings indicate that growth inhibitory effects in MTC cells are associated with downregulation of both mTOR/6SK and pERK signaling pathways. Expression of metformin's molecular targets in human MTC cells suggests its potential utility for the treatment of MTC in patients.

Human Medullary Thyroid Cancer: Xenotransplants and Calcitonin Secretion

1992 ◽  
pp. 144-147
Author(s):  
G. Andry ◽  
P. Lothaire ◽  
P. Vico ◽  
P. Dumont ◽  
D. Larsimont ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Medullary Thyroid ◽  
Calcitonin Secretion

Preclinical study of MEK1/2 inhibitor AZD6244 combined with gemcitabine for treatment of biliary cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 240-240
Author(s):  
Junyao Xu ◽  
Jennifer J. Knox ◽  
Ming Sound Tsao ◽  
Eric Xueyu Chen ◽  
Pinjiang Cao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Preclinical Study ◽  
Erk Signaling ◽  
Therapeutic Effects ◽  
Biliary Cancer

240 Background: MEK1/2 is an integral component of the Ras/Raf/MEK/ERK signaling pathway, implicated in uncontrolled cell proliferation and cell survival, a key hallmark of cancer. AZD6244, a novel inhibitor of MEK1/2, is currently completing Phase II clinical trials in biliary cancer, with modest antitumor activity observed as monotherapy. Gemcitabine is a cytotoxic drug commonly used in biliary cancer therapy but many patients showed early resistance. In this preclinical study, we investigated the sequence-dependent antitumor effects of AZD6244 combined with gemcitabine in biliary cancer models. Methods: Two biliary cancer cell lines (EGI-1 and TFK-1) were used. In vitro the effects of single drug or three combination protocols(concurrently; AZD6244 followed by GEM or Gem followed by AZD6244) on cell proliferation, DNA synthesis, and cell cycle distribution were evaluated by MTS, clonogenic assay, EdU uptake and flow cytometry. Drug interactions were analyzed by Chou-Talaly method. In vivo, 4 tumor models subcutaneously xenografted in SCID mice from the two cell lines and 2 human patients were set up to compare the therapeutic effects of different sequence-scheduled combinations. Results: AZD6244 caused G1-S cell cycle arrest in biliary cancer cells in vitro and in vivo, and this effect is correlated with the MEK/ERK signaling pathway blocking. Synchronized progression of the population through S phase were observed in 15h after removal of AZD6244 in cell culture or 48h after final dose of acute AZD6244 treatment in vivo. Antagonistic or additive effects was observed in vitro when combination were given as concurrently(CI=2.03~2.46) or Gem followed by AZD6244(CI=1.34~1.78). In contrast, a synergistic antiproliferative activity was obtained when AZD6244 was given first followed by a drug-free interval before Gem treatment (CI=0.53~0.69). In vivo, the best therapeutic effects were obtained with the sequence of AZD6244 followed by Gem, compared with concurrent or reverse sequence. Conclusions: This study provides a sound rationale for a Phase II trial of a potentially synergistic sequence of MEK inhibitor AZD6244 followed by gemcitabine in patients with advanced biliary cancer.

scholarly journals Novel Prognostic Factors Associated with Cell Cycle Control in Sporadic Medullary Thyroid Cancer Patients

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Raffaele Pezzani ◽  
Loris Bertazza ◽  
Elisabetta Cavedon ◽  
Simona Censi ◽  
Jacopo Manso ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Aurora Kinase ◽  
Advanced Stage ◽  
Ki 67 ◽  
Altered Expression ◽  
Medullary Thyroid ◽  
Aurora Kinase A ◽  
Kinase A

Background. Medullary thyroid cancer (MTC) is a rare neuroendocrine-derived malignancy. It is represented by sporadic and familiar forms, and both can have RET oncogene mutations. Numerous markers can be used to define MTC; however, none is generally approved for predicting the outcome of sporadic MTC. Aim. The aim of this work was to analyze PTTG1/securin and Aurora kinase A expressions in MTC patients, both at the gene and protein levels, and to define their prognostic role in MTC assessing their association with lab and clinical parameters. Patients and Methods. Seventy-one sporadic MTC human samples were analyzed for RET mutations and by qPCR for PTTG1 and AURKA (Aurora kinase A) expression. Ki-67 levels and western blot reactivity for PTTG1 and Aurora kinase A were also determined in a selected cohort of patients. Results. RET somatic mutations were found in 48% of the patients (34/71). PTTG1 expression was statistically different among the groups with or without regional lymph node metastasis (p<0.0001) and advanced stage disease (p<0.01). PTTG1 and AURKA expressions were statistically higher than those of controls (p=0.01 and p<0.002, respectively). PTTG1 expression and Ki-67 levels were statistically different among the groups with remitted or persistent disease (p<0.05 and p<0.01, respectively). We found a significant correlation between the expressions of AURKA and PTTG1 (p<0.0002, r=0.5298) and between the expressions of PTTG1 and Ki-67 (p=0.01). Ki-67 levels were statistically different among the groups with or without metastatic lymph nodes (p=0.01) or distant metastases (p=0.003). Conclusion. The presence of an altered expression of PTTG1 and AURKA is a negative prognostic factor associated with a more aggressive course of disease, such as an advanced stage or disease persistence. It emerges as a cell cycle process mediated by the 2 factors, in addition to the RET pathway, which can be altered in MTC patients.

The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines

Endocrine ◽  
2015 ◽  
Vol 51 (1) ◽  
pp. 101-112 ◽  
Author(s):  
Alessandra Dicitore ◽  
Elisa Stellaria Grassi ◽  
Michele Caraglia ◽  
Maria Orietta Borghi ◽  
Germano Gaudenzi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Medullary Thyroid Cancer ◽  
Cancer Cell Lines ◽  
Thyroid Cancer Cell ◽  
Medullary Thyroid ◽  
Thyroid Cancer Cell Lines
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