Profile of stress and toxicity gene expression in human hepatic cells treated with Efavirenz

Gomez-Sucerquia, Leysa J.; Blas‐García, Ana; Martı́-Cabrera, Miguel; Esplugues, Juan V.; Apostolova, Nadezda

doi:10.1016/j.antiviral.2012.04.003

Cited by 31 publications

(25 citation statements)

References 33 publications

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“…Upon thermal stress, HaCaT keratinocytes responded with induction of both HSPA1A and A6, although the latter to many more fold at the mRNA level. Given its detection in nonstressed conditions (Gomez-Sucerquia et al 2012 and our report), its capacity for significant fold induction (Chow et al 2010;Qiao et al 2012), and its likely contribution to post-stress cell survival (Noonan et al 2007b), we sought to better define the control of its basal and stress-inducible expression in keratinocytes, a cell type with wide dependence on chaperone function and likely to encounter diverse stress conditions. Nevertheless, even with this better-defined control of its expression, any HSPA6 contribution to chaperoning or stress recovery would be restricted to species carrying the gene such as human, goat, and swine (Banerjee et al 2014;Dezeure et al 1993, andParsian et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Basal and stress-inducible expression of HSPA6 in human keratinocytes is regulated by negative and positive promoter regions

Ramirez

Stamatis

Shmukler

et al. 2015

Cell Stress and Chaperones

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Epidermal keratinocytes serve as the primary barrier between the body and environmental stressors. They are subjected to numerous stress events and are likely to respond with a repertoire of heat shock proteins (HSPs). HSPA6 (HSP70B′) is described in other cell types with characteristically low to undetectable basal expression, but is highly stress induced. Despite this response in other cells, little is known about its control in keratinocytes. We examined endogenous human keratinocyte HSPA6 expression and localized some responsible transcription factor sites in a cloned HSPA6 3 kb promoter. Using promoter 5′ truncations and deletions, negative and positive regulatory regions were found throughout the 3 kb promoter. A region between −346 and −217 bp was found to be crucial to HSPA6 basal expression and stress inducibility. Site-specific mutations and DNA-binding studies show that a previously uncharacterized AP1 site contributes to the basal expression and maximal stress induction of HSPA6. Additionally, a new heat shock element (HSE) within this region was defined. While this element mediates increased transcriptional response in thermally stressed HaCaT keratinocytes, it preferentially binds a stress-inducible factor other than heat shock factor (HSF)1 or HSF2. Intriguingly, this newly characterized HSPA6 HSE competes HSF1 binding a consensus HSE and binds both HSF1 and HSF2 from other epithelial cells. Taken together, our results demonstrate that the HSPA6 promoter contains essential negative and positive promoter regions and newly identified transcription factor targets, which are key to the basal and stress-inducible expression of HSPA6. Furthermore, these results suggest that an HSF-like factor may preferentially bind this newly identified HSPA6 HSE in HaCaT cells.

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Section: Discussionmentioning

confidence: 99%

Basal and stress-inducible expression of HSPA6 in human keratinocytes is regulated by negative and positive promoter regions

Ramirez

Stamatis

Shmukler

et al. 2015

Cell Stress and Chaperones

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“…Although generally considered safe, some evidence indicates that efavirenz disrupts lipid metabolism [70] and induces liver fibrosis [69,71]. An in vitro study demonstrated that a battery of ER stress markers was induced when primary human hepatocytes and Hep3B cells were exposed to clinically relevant concentrations of efavirenz [72,73]. The ER stress responses included induction of CHOP and GRP78, phosphorylation of eIF2a, and the production of XBP1 isoform XBP1S.…”

Section: Efavirenzmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Chen

Melchior

Guo

2014

Journal of Environmental Science and Health, Part C

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Liver injury resulting from exposure to drugs and environmental chemicals is a major health problem. Endoplasmic reticulum stress (ER stress) is considered to be an important factor in a wide range of diseases, such as cancer, neurological and cardiovascular disease, diabetes, and inflammatory diseases. The role of ER stress in drug-induced and environmental toxicant-induced liver toxicity has been underestimated in the past; emerging evidence indicates that ER stress makes a substantial contribution to the pathogenesis of drug-induced liver toxicity. In this review, we summarize current knowledge on drugs and environmental toxicants that trigger ER stress in liver and on the underlying molecular mechanisms. We also discuss experimental approaches for ER stress studies.

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“…One explanation for the mode of operation is the inhibition of an endogenous reverse transcriptase in cancer cells [4–8], another is the interaction with the cannabinoid system [3]. Furthermore, oxidative stress in mitochondria is discussed as mechanism of action [11–13]. During the last years a new generation of NNRTIs has been developed, namely Rilpivirine (RPV), Etravirine (ETR) and Lersivirine (LSV) (Fig 1).…”

Section: Introductionmentioning

confidence: 99%

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

et al. 2015

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BackgroundCancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.MethodsCytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data.ResultsThe in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5μmol/l (= 9944ng/ml), Nevirapine 239μmol/l (= 63786ng/ml), Etravirine 89.0μmol/l (= 38740ng/ml), Lersivirine 543μmol/l (= 168523ng/ml), Delavirdine 171μmol/l (= 78072ng/ml), Rilpivirine 24.4μmol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162–15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856–8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.ConclusionAll studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.

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Profile of stress and toxicity gene expression in human hepatic cells treated with Efavirenz

Cited by 31 publications

References 33 publications

Basal and stress-inducible expression of HSPA6 in human keratinocytes is regulated by negative and positive promoter regions

Basal and stress-inducible expression of HSPA6 in human keratinocytes is regulated by negative and positive promoter regions

Endoplasmic Reticulum Stress in Drug- and Environmental Toxicant-Induced Liver Toxicity

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

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