Involvement of Intracellular Ca2+ Levels in Nonsteroidal Anti-inflammatory Drug-induced Apoptosis

Tanaka, Ken Ichiro; Tomisato, Wataru; Hoshino, Tatsuya; Ishihara, Takeshi; Namba, Takushi; Aburaya, Mayuko; Katsu, Takashi; Suzuki, Keitarou; Tsutsumi, Shinji; Mizushima, Tohru

doi:10.1074/jbc.m502956200

Cited by 106 publications

(102 citation statements)

References 54 publications

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“…BAPTA-AM also inhibited the GRP78 upregulation caused by nimesulide or diclofenac but not by indomethacin. We recently showed that all of NSAIDs tested (including nimesulide and diclofenac) increased the intracellular Ca 2 þ level (Tomisato et al, 2004a;Tanaka et al, 2005). Since indomethacin absorbed fluo-3 fluorescence (530 nm), we could not measure the intracellular Ca 2 þ level in the presence of indomethacin by the assay system using fluo-3 (Tanaka et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells

et al. 2005

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Nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in cancer cells and this effect is involved in their antitumor activity. We recently demonstrated that NSAIDs upregulate GRP78, an endoplasmic reticulum (ER) chaperone, in gastric mucosal cells in primary culture. In the present study, induction of ER chaperones by NSAIDs and the effect of those chaperones on NSAID-induced apoptosis were examined in human gastric carcinoma cells. Celecoxib, an NSAID, upregulated ER chaperones (GRP78 and its cochaperones ERdj3 and ERdj4) but also C/EBP homologous transcription factor (CHOP), a transcription factor involved in apoptosis. Celecoxib also upregulated GRP78 in xenograft tumors, accompanying with the suppression of tumor growth in nude mice. Celecoxib caused phosphorylation of eukaryotic translation initiation factor 2 kinase (PERK) and eukaryotic initiation factor-2a (eIF2a) and production of activating transcription factor (ATF)4 mRNA. Suppression of ATF4 expression by small interfering RNA (siRNA) partially inhibited the celecoxib-dependent upregulation of GRP78. Celecoxib increased the intracellular Ca 2 þ concentration, while 1,2-bis(2-aminophenoxy) ethane-N,N,N 0 N 0 -tetraacetic acid, an intracellular Ca 2 þ chelator, inhibited the upregulation of GRP78 and ATF4. These results suggest that the Ca 2 þ -dependent activation of the PERK-eIF2a-ATF4 pathway is involved in the upregulation of ER chaperones by celecoxib. Overexpression of GRP78 partially suppressed the apoptosis and induction of CHOP in the presence of celecoxib and this suppression was stimulated by coexpression of either ERdj3 or ERdj4. On the other hand, suppression of GRP78 expression by siRNA drastically stimulated cellular apoptosis and production of CHOP in the presence of celecoxib. These results show that upregulation of ER chaperones by celecoxib protects cancer cells from celecoxib-induced apoptosis, thus may decrease the potential antitumor activity of celecoxib.

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Section: Discussionmentioning

confidence: 99%

Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells

et al. 2005

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“…Recently, Mizushima et al clearly showed that the primary targets of NSAIDs in the induction of necrosis and apoptosis are the cytoplasmic membranes. 33,35) In addition, Kato et al reported that excessive NO production via iNOS is related to an increased ulcerogenic response to NSAIDs including loxoprofen and indomethacin. 11,40) We show that the expression of iNOS mRNA and NO production in the gastric mucosa of normal and AA rats are increased by the administration of loxoprofen, and that these increases are significantly higher than those that occur in normal rats administered loxoprofen.…”

Section: Discussionmentioning

confidence: 99%

“…[30][31][32] However, it has been reported that NSAIDs induce necrosis and apoptosis in cultured gastric mucosal cells and in the gastric mucosa in a manner independent of COX inhibition, [33][34][35][36][37] and that the total inhibition of PG production in the stomach causes very little gastric damage in rats. 38) Therefore it is now believed that the inhibition of COX by NSAIDs is not the sole explanation for the gastrointestinal side effects of NSAIDs, 39) and it is assumed that other mechanisms in addition to PG deficiency are involved in the gastric ulcerogenicity of NSAIDs.…”

Section: Discussionmentioning

confidence: 99%

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Nagai

Takeda

Itanami

et al. 2012

Biological & Pharmaceutical Bulletin

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Non-steroidal anti-inflammatory drugs (NSAIDs) comprise one of the most frequently used classes of medicines in the world; however, NSAIDs have significant side effects, such as gastroenteropathy, and rheumatoid arthritis patients taking NSAIDs are more susceptible to NSAID-induced gastric lesions as compared to patients with other diseases. In Asian countries, loxoprofen has been used clinically for many years as a standard NSAID. We demonstrate the preventive effect of the co-administration of water containing magnesium ion (magnesium water, 1-200 µg/kg) on the ulcerogenic response to loxoprofen in adjuvant-induced arthritis (AA) rats. Oral administration of loxoprofen (100 mg/kg) caused hemorrhagic lesions in the gastric mucosa of AA rats 14 d after adjuvant injection, and, following loxoprofen administration, the lesion score of AA rats was significantly higher than that of normal rats. The expression of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in the gastric mucosa of AA rats were also increased by the administration of loxoprofen, and the increase in lesions and NO were prevented by the administration of aminoguanidine, an iNOS inhibitor. The co-administration of magnesium water decreased the ulcerogenic response to loxoprofen in AA rats. In addition, the co-administration of magnesium water attenuated the increase in iNOS mRNA expression and NO production in AA rats receiving loxoprofen. These results suggest that the oral co-administration of magnesium water to AA rats has a potent preventive effect on the ulcerogenic response to loxoprofen, probably by inhibiting the rise in iNOS and NO levels in the gastric mucosa.

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“…One mechanism whereby some NSAIDs are able to induce ER stress and apoptosis in gastric mucosal cells could be an increase in intracellular calcium levels secondary to membrane permeabilization (Tanaka et al. 2005). …”

Section: Introductionmentioning

confidence: 99%

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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Involvement of Intracellular Ca2+ Levels in Nonsteroidal Anti-inflammatory Drug-induced Apoptosis

Cited by 106 publications

References 54 publications

Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells

Celecoxib upregulates endoplasmic reticulum chaperones that inhibit celecoxib-induced apoptosis in human gastric cells

Co-administration of Water Containing Magnesium Ion Prevents Loxoprofen-Induced Lesions in Gastric Mucosa of Adjuvant-Induced Arthritis Rat

Role of endoplasmic reticulum stress in drug‐induced toxicity

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