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3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo.

Kempen I, Papapostolou D, Thierry N, Pochet L, Counerotte S, Masereel B, Foidart JM, Reboud-Ravaux M, Noël A, Pirotte B - Br. J. Cancer (2003)

Bottom Line: In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative.These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9.However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

View Article: PubMed Central - PubMed

Affiliation: Centre Interfacultaire de Recherche en Pharmacochimie des substances naturelles et synthétiques, Laboratoire de Chimie Pharmaceutique, Université de Liège, Belgique. I.Kempen@ulg.ac.be

ABSTRACT
In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

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Effect of synthetic coumarin derivatives on HT1080 fibrosarcoma cell invasion. Chemoinvasion and chemotaxis were evaluated in Transwell cell culture inserts coated or not with type IV collagen, respectively. HT1080 cells (6 × 104) were seeded in the absence (control) or presence of the coumarin inhibitor (0.1, 1 and 10 μM) and the number of cells that have migrated was determined by visually counting the number of cells present on the lower side of the filters: (A) 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and (B) 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate.
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fig3: Effect of synthetic coumarin derivatives on HT1080 fibrosarcoma cell invasion. Chemoinvasion and chemotaxis were evaluated in Transwell cell culture inserts coated or not with type IV collagen, respectively. HT1080 cells (6 × 104) were seeded in the absence (control) or presence of the coumarin inhibitor (0.1, 1 and 10 μM) and the number of cells that have migrated was determined by visually counting the number of cells present on the lower side of the filters: (A) 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and (B) 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate.

Mentions: Since these two products (compounds 4 and 7) appeared to be very potent inhibitors of cell invasion, their anti-invasion and anticancer capacities were further studied in vitro and in vivo. We compared the ability of cells treated or not with the two selected coumarin derivatives to invade through type IV collagen-coated filters (chemoinvasion) and through uncoated filters (chemotaxis). Chemoinvasion corresponds to the capacity to invade through an extracellular matrix, while chemotaxis relies on the ability to migrate in response to a chemotactic factor. Addition of the chloro derivative 4 caused a potent and dose-dependent decrease of HT1080 cell chemoinvasion confirming the results reported in Figure 2B. In the chemotaxis assay, a similar dose response inhibitory effect was observed (20% inhibition at 0.1 μM, 50% inhibition at 1 μM and 80% at 10 μM). In contrast, cell migration through uncoated filters was not markedly affected by the reference compound at 1 μM (20–30% chemotaxis inhibition vs 60% inhibition of chemoinvasion) (Figure 3AFigure 3


3-Bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate inhibits cancer cell invasion in vitro and tumour growth in vivo.

Kempen I, Papapostolou D, Thierry N, Pochet L, Counerotte S, Masereel B, Foidart JM, Reboud-Ravaux M, Noël A, Pirotte B - Br. J. Cancer (2003)

Effect of synthetic coumarin derivatives on HT1080 fibrosarcoma cell invasion. Chemoinvasion and chemotaxis were evaluated in Transwell cell culture inserts coated or not with type IV collagen, respectively. HT1080 cells (6 × 104) were seeded in the absence (control) or presence of the coumarin inhibitor (0.1, 1 and 10 μM) and the number of cells that have migrated was determined by visually counting the number of cells present on the lower side of the filters: (A) 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and (B) 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2376372&req=5

fig3: Effect of synthetic coumarin derivatives on HT1080 fibrosarcoma cell invasion. Chemoinvasion and chemotaxis were evaluated in Transwell cell culture inserts coated or not with type IV collagen, respectively. HT1080 cells (6 × 104) were seeded in the absence (control) or presence of the coumarin inhibitor (0.1, 1 and 10 μM) and the number of cells that have migrated was determined by visually counting the number of cells present on the lower side of the filters: (A) 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and (B) 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate.
Mentions: Since these two products (compounds 4 and 7) appeared to be very potent inhibitors of cell invasion, their anti-invasion and anticancer capacities were further studied in vitro and in vivo. We compared the ability of cells treated or not with the two selected coumarin derivatives to invade through type IV collagen-coated filters (chemoinvasion) and through uncoated filters (chemotaxis). Chemoinvasion corresponds to the capacity to invade through an extracellular matrix, while chemotaxis relies on the ability to migrate in response to a chemotactic factor. Addition of the chloro derivative 4 caused a potent and dose-dependent decrease of HT1080 cell chemoinvasion confirming the results reported in Figure 2B. In the chemotaxis assay, a similar dose response inhibitory effect was observed (20% inhibition at 0.1 μM, 50% inhibition at 1 μM and 80% at 10 μM). In contrast, cell migration through uncoated filters was not markedly affected by the reference compound at 1 μM (20–30% chemotaxis inhibition vs 60% inhibition of chemoinvasion) (Figure 3AFigure 3

Bottom Line: In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative.These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9.However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

View Article: PubMed Central - PubMed

Affiliation: Centre Interfacultaire de Recherche en Pharmacochimie des substances naturelles et synthétiques, Laboratoire de Chimie Pharmaceutique, Université de Liège, Belgique. I.Kempen@ulg.ac.be

ABSTRACT
In search for new anticancer agents, we have evaluated the antiinvasive and antimigrative properties of recently developed synthetic coumarin derivatives among which two compounds revealed important activity: 3-chlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate and 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate. Both drugs were able to inhibit cell invasion markedly in a Boyden chamber assay, the bromo derivative being more potent than the reference matrix metalloprotease (MMP) inhibitor GI 129471. In vivo, tumour growth was reduced when nude mice grafted with HT1080 or MDA-MB231 cells were treated i.p. 3 days week(-1) with the bromo coumarin derivative. These effects were not associated with the inhibition of urokinase, plasmin, MMP-2 or MMP-9. The mechanism of action of the drugs remains to be elucidated. However, these two coumarin derivatives may serve as new lead compounds of an original class of antitumour agents.

Show MeSH
Related in: MedlinePlus