Evaluation of antitumoral properties of the protease inhibitor indinavir in a murine model of hepatocarcinoma.
OBJECTIVE
Accumulating evidences show a higher incidence of hepatic neoplasm in HIV/hepatitis C virus (HCV)-coinfected individuals compared with HCV-monoinfected patients. Treatment with HIV-1 protease inhibitors inhibited cancer-promoted angiogenesis in HIV-infected patients affected by Kaposi sarcoma. We aimed to evaluate the antineoplastic potential activities of the protease inhibitor indinavir (Crixivan) in in vitro and in vivo hepatocarcinoma models.


METHODS
We analyzed effects of indinavir on cell growth and invasiveness in Huh7 and SK-HEP-1 hepatocarcinoma cell lines and on in vivo tumor growth of the same cells in nude mice. Morphologic and molecular analyses on explanted tumors were carried out to evaluate vascularization and apoptosis.


RESULTS
We observed a reduced ability to invade an in vitro extracellular matrix for both cell lines treated with indinavir compared with controls (P = 0,001). Moreover, indinavir treatment was able to inhibit matrix metalloproteinase-2 proteolytic activation, whereas there was no effect on cell proliferation. The drug was also able to delay in vivo tumor growth. The inhibition of tumor growth was statistically significant from days 6 to 21 (P = 0.004 and P = 0.003, respectively). Moreover, the drug showed antiangiogenic and proapoptotic actions, as revealed by vessel count and apoptotic index by terminal deoxynucleotide transferase-mediated nick end labeling in explanted tumors. Finally, treatment with indinavir did not block the production of vascular endothelial growth factor in the tumors.


CONCLUSIONS
Indinavir could be helpful to prevent the development of hepatocarcinomas in HIV/HCV-coinfected individuals. In view of the current trend to substitute protease inhibitors with other antiretroviral agents, this information may have clinical implications.
Esposito
Vincenzo
V
Third Division Cotugno Hospital, Naples, Italy. esposvin@libero.it
Palescandolo
Emanuele
E
Spugnini
Enrico P
EP
Montesarchio
Vincenzo
V
De Luca
Antonio
A
Cardillo
Irene
I
Cortese
Giancarlo
G
Baldi
Alfonso
A
Chirianni
Antonio
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020287:In Situ Nick-End Labeling; D019469:Indinavir / Q000494:pharmacology* / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D042461:Vascular Endothelial Growth Factor A; D019469:Indinavir; D020778:Matrix Metalloproteinase 2