CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo

Alessandro Antonelli, Guido Bocci, Concettina La Motta, Silvia Martina Ferrari, Poupak Fallahi, Ilaria Ruffilli, Andrea Di Domenicantonio, Anna Fioravanti, Stefania Sartini, Michele Minuto, Simona Piaggi, Alessandro Corti, Greta Alì, Teresa Di Desidero, Piero Berti, Gabriella Fontanini, Romano Danesi, Federico Da Settimo, Paolo Miccoli

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Abstract

Context and Objective: We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo. Design and Main Outcome Measures: CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 μM; 2) in ATC cells at the concentrations of 10, 30, and 50 μM; and 3) in an ATC cell line (AF) in CD nu/nu mice. Results: CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P <0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 μM in normal thyroid follicular cells (P <0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P <0.001, ANOVA) and inhibited migration (P <0.01) and invasion (P <0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg·d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues. Conclusions: The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number4
DOIs
Publication statusPublished - Apr 2012

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Vascular Endothelial Growth Factor Receptor-2
Amides
Cells
Analysis of variance (ANOVA)
Tumors
Cell Line
Analysis of Variance
Vascular Endothelial Growth Factor A
In Vitro Techniques
Anaplastic Thyroid Carcinoma
4-chloro-N-(1,1,3-trioxo-2,3-dihydrobenzo(d)isothiazol-4-yl)benzamide
Neoplasms
Phosphorylation
Endothelial cells
Microvessels
Thyroid Neoplasms
Epidermal Growth Factor Receptor
Gene expression
Endothelial Cells
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

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CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo. / Antonelli, Alessandro; Bocci, Guido; La Motta, Concettina; Ferrari, Silvia Martina; Fallahi, Poupak; Ruffilli, Ilaria; Di Domenicantonio, Andrea; Fioravanti, Anna; Sartini, Stefania; Minuto, Michele; Piaggi, Simona; Corti, Alessandro; Alì, Greta; Di Desidero, Teresa; Berti, Piero; Fontanini, Gabriella; Danesi, Romano; Da Settimo, Federico; Miccoli, Paolo.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 4, 04.2012.

Research output: Contribution to journalArticle

Antonelli, A, Bocci, G, La Motta, C, Ferrari, SM, Fallahi, P, Ruffilli, I, Di Domenicantonio, A, Fioravanti, A, Sartini, S, Minuto, M, Piaggi, S, Corti, A, Alì, G, Di Desidero, T, Berti, P, Fontanini, G, Danesi, R, Da Settimo, F & Miccoli, P 2012, 'CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 4. https://doi.org/10.1210/jc.2011-1987
Antonelli, Alessandro ; Bocci, Guido ; La Motta, Concettina ; Ferrari, Silvia Martina ; Fallahi, Poupak ; Ruffilli, Ilaria ; Di Domenicantonio, Andrea ; Fioravanti, Anna ; Sartini, Stefania ; Minuto, Michele ; Piaggi, Simona ; Corti, Alessandro ; Alì, Greta ; Di Desidero, Teresa ; Berti, Piero ; Fontanini, Gabriella ; Danesi, Romano ; Da Settimo, Federico ; Miccoli, Paolo. / CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 4.
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T1 - CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo

AU - Antonelli, Alessandro

AU - Bocci, Guido

AU - La Motta, Concettina

AU - Ferrari, Silvia Martina

AU - Fallahi, Poupak

AU - Ruffilli, Ilaria

AU - Di Domenicantonio, Andrea

AU - Fioravanti, Anna

AU - Sartini, Stefania

AU - Minuto, Michele

AU - Piaggi, Simona

AU - Corti, Alessandro

AU - Alì, Greta

AU - Di Desidero, Teresa

AU - Berti, Piero

AU - Fontanini, Gabriella

AU - Danesi, Romano

AU - Da Settimo, Federico

AU - Miccoli, Paolo

PY - 2012/4

Y1 - 2012/4

N2 - Context and Objective: We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo. Design and Main Outcome Measures: CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 μM; 2) in ATC cells at the concentrations of 10, 30, and 50 μM; and 3) in an ATC cell line (AF) in CD nu/nu mice. Results: CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P <0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 μM in normal thyroid follicular cells (P <0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P <0.001, ANOVA) and inhibited migration (P <0.01) and invasion (P <0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg·d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues. Conclusions: The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.

AB - Context and Objective: We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo. Design and Main Outcome Measures: CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 μM; 2) in ATC cells at the concentrations of 10, 30, and 50 μM; and 3) in an ATC cell line (AF) in CD nu/nu mice. Results: CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P <0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 μM in normal thyroid follicular cells (P <0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P <0.001, ANOVA) and inhibited migration (P <0.01) and invasion (P <0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg·d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues. Conclusions: The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.

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