Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition.
Halofuginone, an inhibitor of collagen synthesis, appears to be a promising antitumoral drug in preclinical studies. We used a relevant rat model of autochthonous, chemically induced, spontaneously metastasizing hepatocellular carcinoma (HCC) to test the efficacy of halofuginone on tumor progression and matrix metalloproteinase (MMP) expression. Following sequential administration of diethylnitrosamine and N-nitrosomorpholine for 14 weeks, all animals developed HCC and then received halofuginone or its solvent for 10 weeks. The final number of liver tumors was lower in the halofuginone group than in the solvent group (57.2 +/- 4.6 vs 68 +/- 5.0; P < .01). The percentage of the lung surface infiltrated by metastasis was much smaller in the halofuginone group (0.3 +/- 0.2%) than in the solvent group (13.5 +/- 10.1%; P < .02). MMP-9 activity was decreased in the halofuginone group by 89% and 63% in non-neoplastic parts of the liver and tumor, respectively. The percentage of active MMP-2 was reduced by 90% in non-neoplastic parts of the liver and by 61% in tumors. This was likely subsequent to a decreased expression of both MMP-14 and tissue inhibitor of matrix metalloproteinase-2, which are required for pro-MMP-2 activation. These results, obtained from a clinically relevant model, further suggest the potential benefit of halofuginone in HCC.
Taras
Danièle
D
INSERM E362, Bordeaux F-33076, France.
Blanc
Jean-Frédéric
JF
Rullier
Anne
A
Dugot-Senant
Nathalie
N
Laurendeau
Ingrid
I
Bièche
Ivan
I
Pines
Mark
M
Rosenbaum
Jean
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000188:drug therapy*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D053504:Matrix Metalloproteinases, Membrane-Associated; D009362:Neoplasm Metastasis; D010880:Piperidines; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D051381:Rats; D011916:Rats, Inbred F344
D020533:Angiogenesis Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C010176:halofuginone