HIV Protease Inhibitors Induce Endoplasmic Reticulum Stress and Disrupt Barrier Integrity in Intestinal Epithelial Cells

Zhou, Huiping

doi:10.1016/b978-0-12-385114-7.00006-4

Cited by 13 publications

(14 citation statements)

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“…There is general agreement that toxicity of NRTIs may be related to their effects on the mitochondrial DNA polymerase gamma (Pol γ), responsible for mitochondrial DNA replication, leading to cell apoptosis(Feng et al, 2001; Marra et al, 1997). PIs, on the other hand, are known to induce endoplasmic reticulum stress, followed by apoptosis or autophagy (Bruning et al, 2009; Zha et al, 2011; Zhou, 2011). However, it has been noted that toxicity of different anti-HIV drugs is cell-, tissue-, and organ-specific (Benbrik et al, 1997), and consequently the response of auditory HEI-OC1 cells could be different to that observed in other cell lines from different organs.…”

Section: Discussionmentioning

confidence: 99%

In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity

et al. 2014

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Several studies have reported an increased incidence of auditory dysfunction among HIV/AIDS patients. We used auditory HEI-OC1 cells in cell viability, flow cytometry and caspases 3/7-activation studies to investigate the potential ototoxicity of fourteen HIV antiretroviral agents: Abacavir, AZT, Delavirdine, Didenosine, Efavirenz, Emtricitabine, Indinavir, Lamivudine, Nefinavir, Nevirapine, Tenofovir, Ritonavir, Stavudine and Zalcitabine, as well as combinations of these agents as used in the common anti-HIV cocktails Atripla™, Combivir™, Epzicom™, Trizivir™, and Truvada™. Our results suggested that most of the single assayed anti-HIV drugs are toxic for HEI-OC1 auditory cells. The cocktails, on the other hand, decreased auditory cells’ viability with high significance, with the following severity gradient: Epzicom ~ Trizivir ≫ Atripla ~ Combivir > Truvada. Interestingly, our results suggest that Trizivir- and Epzicom-induced cell death would be mediated by a caspase-independent mechanism. L-Carnitine, a natural micronutrient known to protect HEI-OC1 cells against some ototoxic drugs as well as to decrease neuropathies associated with anti-HIV treatments, increased viability of cells treated with Lamivudine and Tenofovir as well as with the cocktail Atripla, but had only minor effects on cells treated with other drugs and drug combinations. Altogether, these results suggest that some frequently used anti-HIV agents could have deleterious effects on patients hearing, and provide arguments in favor of additional studies aimed at elucidating the potential ototoxicity of current as well as future anti-HIV drugs.

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Section: Discussionmentioning

confidence: 99%

In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity

et al. 2014

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“…In contrast, amprenavir, darunavir, and tipranavir induced only a weak or no ER stress in the different tested experimental models Zhou 2011;Taura et al 2013;Zha et al 2013). Notably, some of these studies brought evidence that PI-induced ER stress was involved in lipid metabolism alterations, inflammation, cell apoptosis, and tissue damage, in particular by using CHOP À/À mice or cells (Zhou et al 2005;Cao et al 2010;Wu et al 2010;Zha et al 2010Zha et al , 2013Zhou 2011;Wang et al 2013b). According to these investigations, ER stress could thus be an important mechanism whereby some PIs are able to induce metabolic disturbances such as lipodystrophy, hepatic steatosis and cytolysis, dyslipidemia, and some cardiovascular complications.…”

Section: Protease Inhibitorsmentioning

confidence: 96%

“…Hence, it is difficult to ascertain from these reports that ER stress is bona fine involved in drug-induced toxicity. In contrast, some of the aforementioned studies brought causal relationship by using CHOP -/mice or cells (Zinszner et al 1998;Marciniak et al 2004;Wu et al 2010;Zhou 2011;Uzi et al 2013;Wang et al 2013b;Zha et al 2013;Tanaka et al 2015). Thus, future investigations should use these experimental models, or similar ones with knockout of other major proteins involved in ER stress such as IRE1, PERK, or ATF6 (Fig.…”

Section: Concluding Remarks and Remaining Issuesmentioning

confidence: 99%

“…PIs are toxic via different pathways, in particular by inducing mitochondrial dysfunction and oxidative stress and by promoting inflammation (Gougeon et al 2004;Caron et al 2007;Caron-Debarle et al 2010;Mencarelli et al 2012;Bociaga-Jasik et al 2013;Cassol et al 2013;Reyskens et al 2013). Several studies also reported that some PIs are able to induce ER stress in different types of cells (e.g., macrophages, adipocytes, hepatocytes) and tissues (e.g., liver, intestine) (Zhou et al 2005;Gupta et al 2007;Cao et al 2010;Touzet and Philips 2010;Wu et al 2010;Zha et al 2010Zha et al , 2013Br€ uning 2011;Zhou 2011;Br€ uning et al 2012;Apostolova et al 2013;Taura et al 2013;Wang et al 2013b). In these investigations, ER stress was consistently observed with atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir.…”

Section: Protease Inhibitorsmentioning

confidence: 99%

“…In contrast, amprenavir, darunavir, and tipranavir induced only a weak or no ER stress in the different tested experimental models (Wu et al. 2010; Zhou 2011; Taura et al. 2013; Zha 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

188

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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The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice

Wang

Zhang

et al. 2013

Hepatology

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HIV protease inhibitors (HIV PIs) are the core components of highly active antiretroviral therapies (HAART), which has been successfully used in treatment of HIV-1 infection in the past two decades. However, benefits of HIV PIs are compromised by clinically important adverse effects such as dyslipidemia, insulin resistance and cardiovascular complications. We have previously shown that activation of endoplasmic reticulum (ER) stress plays a critical role in HIV PI-induced dysregulation of hepatic lipid metabolism. HIV PI-induced hepatic lipotoxicity is closely linked to the upregulation of C/EBP homologous protein (CHOP) in hepatocytes. To further investigate whether CHOP is responsible for HIV PI-induced hepatic lipotoxicity, C57BL/6J wild-type (WT) or CHOP knockout (CHOP−/−) mice or the corresponding primary mouse hepatocytes were used in this study. Both in vitro and in vivo studies indicated that HIV PIs (ritonavir and lopinavir) significantly increased hepatic lipid accumulation in WT mice. In contrast, CHOP−/− mice showed a significant reduction in hepatic triglyceride accumulation and liver injury as evidenced by H&E staining and Oil Red O staining. Real-time RT-PCR and immunoblot data showed that in the absence of CHOP, HIV PI-induced expression of stress-related proteins and lipogenic genes was dramatically reduced. Furthermore, TNF-α and IL-6 levels in serum and livers were significantly lower in HIV PI-treated CHOP−/− mice compared to HIV PI-treated WT mice. CONCLUSION Taken together, these data suggest that CHOP is an important molecular link of ER stress, inflammation and hepatic lipotoxicity and increased expression of CHOP represents a critical factor underlying events leading to hepatic injury.

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HIV Protease Inhibitors Induce Endoplasmic Reticulum Stress and Disrupt Barrier Integrity in Intestinal Epithelial Cells

Cited by 13 publications

References 37 publications

In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity

In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice

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