Clinical course of classic Kaposi's sarcoma in HIV-negative patients treated with the HIV protease inhibitor indinavir

Monini, Paolo; Sgadari, Cecilia; Grosso, Maria Gabriella; Bellino, Stefania; Biagio, Antonio Di; Toschi, Elena; Bacigalupo, Ilaria; Sabbatucci, Michela; Cencioni, Giulia; Salvi, Emanuela; Leone, Patrizia; Ensoli, Barbara

doi:10.1097/qad.0b013e3283262a8d

Cited by 32 publications

(32 citation statements)

References 16 publications

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“…In western countries, KS incidence has remarkably diminished as the implementation of highly active anti-retroviral therapy. This strategy, that allows immune rescue and Human immunodeficiency virus (HIV) replication control, frequently leads to clinical regression of most KS lesions without the need for specific chemotherapies (Sgadari et al, 2002;Monini et al, 2009). However, although KS tends to decline upon antiretroviral treatment, paradoxical aggravations have been described during the early treatment period, where recovery is generally slow (Mitsuyasu, 2000;Maurer et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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“…7, 24, 27, 28, 49, 52-54 One uncontrolled trial of indinavir suggested a clinical benefit for classic (HIV-negative) KS. 55 Indinavir, ritonavir, lopinavir and other PIs have anti- angiogenic and anti-tumor properties, though they appear to be less potent than nelfinavir and lack anti-HHV-8 activity in vitro . 33, 34 As such, KS treatment and prevention trials should be considered to specifically evaluate nelfinavir or other agents with inhibitory activity against HHV-8.…”

Section: Discussionmentioning

confidence: 99%

Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy

Gantt

Cattamanchi

Krantz

et al. 2014

Journal of Clinical Virology

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Background Human herpesvirus 8 (HHV-8) replication increases the risk of Kaposi sarcoma (KS). Highly-active antiretroviral therapy (HAART) reduces the incidence of KS, and regimens that contain protease inhibitors (PIs) may be particularly effective. Objective To determine whether PI-based HAART regimens may more effectively inhibit HHV-8 shedding compared to regimens without PIs. Study design Prospective, observational study of 142 HIV-1 and HHV-8 co-infected men conducted in Seattle, Washington. Quantitative HHV-8 PCR testing was performed on daily swabs of the oropharynx, the primary site of HHV-8 replication. Associations between antiretroviral regimen and detection of HHV-8 DNA in swabs were evaluated using generalized estimating equations. Results HHV-8 DNA was detected in 3,016 (26%) of 11,608 specimens collected. PI-based HAART was associated with a statistically significantly lower frequency of detection (RR 0.2; 95% CI 0.1 to 0.5) compared to ART-naïve persons, whereas HAART without a PI was not (RR 0.7; 95% CI 0.4 to 1.3). Compared to ART-naïve persons, there was also a trend toward lower quantities of HHV-8 detected during treatment with HAART regimens that contained a PI. These associations between PIs and measures of HHV-8 shedding could not be attributed to use of nelfinavir, which inhibits HHV-8 replication in vitro, and were independent of CD4 count and HIV plasma viral load (VL). Conclusions HAART regimens that contain PIs appear to decrease HHV-8 shedding compared to NNRTIs. Further study of PI-based HAART is warranted to determine the optimal regimens for prevention and treatment of KS.

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“…Based on their pre-clinical findings, Monini et al conducted a pilot trial of indinavir for endemic (HIV-negative) Kaposi sarcoma [76]. Twenty-eight patients received 800 mg of indinavir BID for 12 months, and although a control group was not included, clinical response was associated with blood levels of indinavir.…”

Section: Clinical Oncology Trials (Table 2)mentioning

confidence: 99%

Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention

Gantt

Casper

Ambinder

2013

Current Opinion in Oncology

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Purpose of Review The development of HIV protease inhibitors (PIs) more than two decades ago heralded a new era in HIV care, changing the infection from universally-fatal to chronic but controllable. With the widespread use of PIs, there was a reduction in the incidence and mortality of HIV-associated malignancies. Studies later found these drugs to have promising direct antitumor effects. Recent findings PIs have a wide range of effects on several cellular pathways that are important for tumorigenesis and independent of inhibition of the HIV protease, including reducing angiogenesis and cell invasion, inhibition of the Akt pathway, induction of autophagy, and promotion of apoptosis. Among PIs, Nelfinavir appears to have the most potent and broad antineoplastic activities, and also affects replication of the oncogenic herpesviruses Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus. Nelfinavir is being studied for the prevention and treatment of a wide range of malignancies in persons with and without HIV infection. Summary Nelfinavir and other PIs are safe, oral drugs that have promising antitumor properties, and may prove to play an important role in the prevention and treatment of several cancers. Additional insights into PIs’ mechanisms of action may lead to the development of novel cancer chemotherapy agents.

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Clinical course of classic Kaposi's sarcoma in HIV-negative patients treated with the HIV protease inhibitor indinavir

Cited by 32 publications

References 16 publications

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy

Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention

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