The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo

Bono, Camille; Karlin, Lionel; Harel, Stéphanie; Mouly, Enguerran; Labaume, S.; Galicier, Lionel; Apcher, Sébastien; Sauvageon, Hélène; Fermand, Jean‐Paul; Borie, Raphaël; Arnulf, Bertrand

doi:10.3324/haematol.2011.049981

Cited by 43 publications

(55 citation statements)

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“…Nelfinavir has pleiotropic mechanisms in cancer cells including induction of ER stress, apoptosis and autophagy [14], inhibition of angiogenesis [18], proteasome activity [19], AKT [14], HIF1alpha [20], site-2 protease [21], and hsp90 [22], as well as radiation sensitization [23]. The fact that the crucial mechanism(s) in vivo are not known, combined with the lack of knowledge regarding MTD, informed our decision to perform a dose escalation phase I trial.…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

et al. 2014

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Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.

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Section: Discussionmentioning

confidence: 99%

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

et al. 2014

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“…2007; Bono et al. 2012). Indeed, several studies carried out with other compounds (e.g., bortezomib) showed that specific impairment of proteasome function can potently trigger ER stress (Lee et al.…”

Section: Introductionmentioning

confidence: 99%

“…2004; Bono et al. 2012). In this context, ER stress occurs because the proteasome cannot degrade the few misfolded proteins that are normally but constantly produced within the ER (Fribley and Wang 2006; Xu et al.…”

Section: Introductionmentioning

confidence: 99%

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Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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“…As such, interference with either of these functions by PIs may contribute to ER stress [24,29,35,39,53]. Inhibition of 20S proteasome activity by ritonavir [44,54,58] and saquinavir [50] has been reported.…”

Section: Description Of Hiv Protease Inhibitorsmentioning

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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The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo

Cited by 43 publications

References 40 publications

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors

Role of endoplasmic reticulum stress in drug‐induced toxicity

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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