Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma

Pati, Shibani; Pelser, Colleen; Dufraine, Joseph; Bryant, Joseph; Reitz, Marvin S.; Weichold, Frank F.

doi:10.1182/blood.v99.10.3771

Cited by 132 publications

(108 citation statements)

References 67 publications

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“…Protease inhibitors can affect important cellular processes such as angiogenesis, tumor growth and invasion, inflammation, antigen processing and presentation, cell survival, tissue remodelling and metastasis (Sgadari et al, 2003). Protease inhibitors have direct antiproliferative and antiangiogenic effects in vitro, and inhibit the development of KS-like lesions in animal models by blocking an enzyme required for the production of infectious HHV-8 particles (Pati et al, 2002;Sgadari et al, 2002Sgadari et al, , 2003. In clinical trials, PI-containing regimens led to full remission from KS in approximately 50% of patients, and conferred an added survival benefit (Burdick et al, 1997;Aboulafia, 1998;Krischer et al, 1998;Cattelan et al, 1999;De Milito et al, 1999;Paparizos et al, 2002;Leitch et al, 2003;Sgadari et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

et al. 2006

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Highly active antiretroviral therapy (HAART) reduces the incidence and improves the prognosis of Kaposi's sarcoma (KS). This study was designed to identify factors associated with KS clinical responses in HIV-infected patients during HAART. We reviewed the files of 138 HIV-1-infected patients with KS. Epidemiologic and HIV-related clinical and biological parameters were recorded at KS diagnosis (baseline) and every 6 months thereafter. In a subset of 73 antiretroviral-naive patients, we compared the clinical outcome of KS according to the use or nonuse of protease inhibitors (PI). After 6 months of follow-up, KS remission was more frequent in patients who were naive of HAART and who were at ACTG stage S0 at baseline (P ¼ 0.03 and 0.02). Undetectable HIV viral load was strongly associated with KS remission (Pp0.004 at all time points), while CD4 cell count was not. Among the 73 antiretroviralnaive patients at baseline, and who were studied for 24 months, KS outcome did not differ between patients who were prescribed PIcontaining and PI-sparing regimens. Intercurrent multicentric Castleman's disease was associated with poor outcome after 60 months of follow-up (Pp0.0001). Fourteen deaths occurred after a median follow-up of 37.5 months, eight of which were KS related. Suppression of HIV replication appears to be crucial to control KS. Non-PI-based regimens were equivalent to PI-based regimens as regards the clinical and virological outcome of antiretroviral-naive HIV-infected patients with KS.

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Section: Discussionmentioning

confidence: 99%

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

et al. 2006

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“…Finally, when the KS cell line is implanted into an immunodeficient BNX mouse, treatments with ritonavir at doses of 30 mg/kg/day for 15 days resulted in decreased tumor size in treated animals compared to controls (see Figure 4). 56 It is apparent, therefore, that under certain circumstances, particularly with high-dose PI, a paradoxical proapoptotic effect can be observed. While the mechanisms underlying this proapoptotic effect are undefined, it is theoretically possible that these drugs may possess both an agonistic activity at high dose, yet an antagonistic activity at low dose, potentially by interacting with the same apoptosis regulatory protein.…”

Section: Paradoxical Pro-apoptotic Effects Of Hiv Pismentioning

confidence: 99%

In vitro and in vivo effects of HIV protease inhibitors on apoptosis

Badley

2005

Cell Death Differ

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Development of potent inhibitors of HIV protease has revolutionized the treatment of HIV infection. HIV protease inhibitors (PI) have caused more dramatic improvements in CD4 T-cell numbers than in other therapies that were available previously, prompting investigators to assess whether PI possess intrinsic immunomodulatory effects. An emerging body of data indicates that HIV PIs are antiapoptotic, although the exact molecular target responsible for this antiapoptotic effect remains to be defined in vitro and in vivo. Paradoxically, high-dose PI also may have proapoptotic effects, particularly when assessed in vitro in transformed cell lines and implanted mouse models. Future research will define molecular targets of PI that are responsible for their apoptotis modulatory effects (both pro-and anti-apoptotic). In addition, evaluation of the clinical utility of PI-based therapy in those non-HIV disease states that are characterized by excessive apoptotis will reveal the full clinical potential of this intriguing class of drugs. Cell Death and Differentiation (2005) 12, 924-931.

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“…27,29,30 Ritonavir also has been reported to inhibit the transactivation of NF-jB induced by activators such as TNFa, HIV-1 Tat protein and the human herpesvirus 8 protein ORF74. 31 It is possible that inhibition of NF-jB activation by ritonavir is linked to additional pathways other than inhibition of proteasome. 31 Protease inhibitors also have been shown to have direct antiangiogenic and antitumor activity.…”

mentioning

confidence: 99%

An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

Dewan

Tomita

Katano

et al. 2008

Intl Journal of Cancer

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Epstein-Barr Virus (EBV)-associated immunoblastic lymphoma occurs in immunocompromised patients such as those with AIDS or transplant recipients after primary EBV infection or reactivation of a preexisting latent EBV infection. In the present study, we evaluated the effect of ritonavir, an HIV protease inhibitor, on EBV-positive lymphoblastoid B cells in vitro and in mice model. We found that it induced cell-cycle arrest at G 1 -phase and apoptosis through down-regulation of cell-cycle gene cyclin D2 and antiapoptotic gene survivin. Furthermore, ritonavir suppressed transcriptional activation of NF-jB in these cells. Ritonavir efficiently prevented growth and infiltration of lymphoma cells in various organs of NOD/SCID/cc null mice at the same dose used for treatment of patients with AIDS. Our results indicate that ritonavir targets NF-jB activated in tumor cells and shows anti-tumor effects. These data also suggest that this compound may have promise for treatment or prevention of EBV-associated lymphoproliferative diseases that occur in immunocompromised patients.

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Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma

Cited by 132 publications

References 67 publications

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

Remission from Kaposi's sarcoma on HAART is associated with suppression of HIV replication and is independent of protease inhibitor therapy

In vitro and in vivo effects of HIV protease inhibitors on apoptosis

An HIV protease inhibitor, ritonavir targets the nuclear factor‐kappaB and inhibits the tumor growth and infiltration of EBV‐positive lymphoblastoid B cells

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