Evaluation of Antitumoral Properties of the Protease Inhibitor Indinavir in a Murine Model of Hepatocarcinoma

Abstract

Purpose: 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 HIVinfected 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. Experimental Design:We analyzed effects of indinavir on cell growth and invasiveness in Huh7 and SK-HEP-1hepatocarcinoma 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. Conclusion: 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.

Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential

“…33 IDV reduces hepatocarcinoma growth in vivo . 34 These effects are accompanied by the induction of ER stress, which may in turn trigger cell apoptosis. 32, 41 …”

“…They have been shown to efficiently reduce the tumor mass of aggressive neoplasms such as glioblastomas or ovarian cancers, 31, 32 to reduce xenograft formation from prostatic tumors 33 as well as the growth of hepatocarcinomas in vivo . 34 However, these studies were performed indiscriminately on total cancer cell populations, thus hindering any identification of PI-specific effects on CSCs, including those expressing an embryonic signature.…”

HIV-1 Protease Inhibitors Nelfinavir and Atazanavir Induce Malignant Glioma Death by Triggering Endoplasmic Reticulum Stress

“…Since then, several reports indicated that PIs might indeed harbor antitumor activity, albeit to varying degrees. For example, indinavir has been shown to reduce the invasion of hepatocarcinoma cell lines in vitro and to delay growth of these tumors in a nude mouse model in vivo (3). Using prostate carcinoma cell lines, Yang et al (4) reported that nelfinavir was able to block interleukin-6-stimulated signal transduction pathways in vitro and inhibited xenograft tumor growth in vivo.…”

Treatment for Kaposi sarcoma herpesvirus: great challenges with promising accomplishments

“…Studies of PI in other tumors suggest that they may also have a direct effect on KS regression. Indinavir inhibited matrix metalloprotease 2 (MMP-2) proteolytic activation and angiogenesis in a hepatocellular carcinoma model [24]. However, a recent retrospective analysis of 138 patients with AIDS-associated KS showed that the response to KS was not associated with the type of HAART regimen used [25].…”