Table 1.
Drugs for which adverse events have been linked to ER stress
| Drug(s) | Pharmacological class | Main side effects | Mechanism of ER stress | Additional information |
|---|---|---|---|---|
| Acetaminophen (APAP) | Antalgic and antipyretic | Hepatotoxicity and nephrotoxicity, commonly after an overdose | Currently unknown. Possible involvement of the APAP‐derived reactive metabolite NAPQI, which binds to several key microsomal proteins including PDI and calreticulin | ER stress could be a late event after APAP intoxication, compared to other deleterious events such as mitochondrial dysfunction and oxidative stress |
| Amiodarone | Antiarrhythmic and antianginal | Hypotension, cutaneous reactions, thyroid toxicity, liver injury, and pulmonary toxicity | Currently unknown | ER stress could be involved in some amiodarone‐induced adverse effects (e.g., thyroid and lung toxicity) in addition to mitochondrial dysfunction |
| Arsenic trioxide (As2O3) | Anticancer agent used to treat acute promyelocytic leukemia and other hematologic malignancies | GI disorders, rash, hematologic toxicity, infections, cardiac toxicity renal toxicity, myopathy, neuropathy, and hepatotoxicity | Possible involvement of oxidative stress and impairment of protein folding | In addition to ER stress, mitochondrial dysfunction is also likely to be involved in the pathogenesis of some adverse effects induced by arsenic trioxide |
| Bleomycin | Anticancer drug used in different malignancies such as lymphomas, head and neck cancers as well as ovarian and testicular cancers | GI disorders, cutaneous reactions, myelosuppression, and life‐threatening pulmonary toxicity | Currently unknown. Possible mechanisms could involve oxidative stress | ER stress could be involved in bleomycin‐induced pulmonary toxicity |
| Bortezomib (PS‐341) | Anticancer drug used to treat multiple myeloma and mantle cell lymphoma | GI symptoms, fatigue, peripheral neuropathy, and thrombocytopenia | Proteasome inhibition | ER stress is one mechanism whereby bortezomib is able to induced apoptosis in cancer cells. ER stress could be involved in bortezomib‐induced peripheral neuropathy |
| Cisplatin | Anticancer drug used in various malignancies such as testicular, gastric, lung, breast, and ovarian cancers | GI disorders, kidney injury, neurotoxicity, hepatotoxicity, and cardiotoxicity | Currently unknown. Possible mechanisms could involve oxidative stress and/or the covalent binding of cisplatin to key microsomal proteins | ER stress could be involved in cisplatin‐induced kidney injury |
| Clozapine and olanzapine | Antipsychotics | GI disorders, drowsiness, extrapyramidal symptoms, elevation in liver enzymes, and obesity (with related metabolic disorders such as insulin resistance and fatty liver) | Currently unknown. Possible involvement of increased cytosolic calcium | Although fatty liver induced by clozapine and olanzapine could be secondary to obesity, hepatocyte ER stress directly induced by these drugs might also be involved |
| Cyclosporin | Immunosuppressant | Infections, hypertension, neurotoxicity, nephrotoxicity, and hepatotoxicity (including cholestasis and cytolysis) | Currently unknown. In hepatocytes, a possible mechanism could be the covalent binding of cyclosporin metabolites to pivotal microsomal proteins | Possible involvement of ER stress in cyclosporin‐induced cholestasis. Cyclosporin‐induced ER stress in kidney could be indirect consequence of vascular dysfunction |
| Diclofenac | NSAID | GI complications (including gastric injury and intestinal damage), hypersensitivity reactions, hepatotoxicity, and kidney injury | Currently unknown. Possible involvement of increased intracellular calcium in gastric mucosal cells. Because diclofenac metabolism generates two p‐benzoquinone imines similar to APAP‐derived NAPQI, binding to key ER proteins could be involved (in liver and other tissues expressing CYPs) | Possible involvement of ER stress in diclofenac‐induced GI complications and liver toxicity |
| Efavirenz | Antiretroviral (non‐nucleoside reverse transcriptase inhibitor) | Rash, neuropsychological symptoms, lipodystrophy, and hepatotoxicity (in particular cytolysis and cholestasis) | Possible secondary consequence of mitochondrial dysfunction and release of mitochondrial calcium into the cytosol | Possible involvement of ER stress in efavirenz‐induced hepatotoxicity |
| Erlotinib | Anticancer drug used in different malignancies including non‐small cell lung cancer and pancreatic cancer | Rash and GI manifestations (in particular severe diarrhea) | Currently unknown | Possible involvement of ER stress in erlotinib‐induced small intestinal injury and diarrhea |
| Furosemide | Diuretic used to treat hypertension and edema | Dehydration, hypotension, hyponatremia, and hypokalemia | Currently unknown | Hepatic ER stress has been detected in mice treated by furosemide. Extrapolation to humans is doubtful since this drug induces virtually no hepatotoxicity in patients |
| Indomethacin | NSAID | GI complications (including gastric injury and intestinal damage), hypersensitivity reactions, hepatotoxicity, and kidney injury | Currently unknown. Possible involvement of increased intracellular calcium (in gastric mucosal cells) | Possible involvement of ER stress in indomethacin‐induced GI complications and liver toxicity |
| Paclitaxel (Taxol) | Anticancer agent used in different malignancies including ovarian, breast, and lung cancers | GI disorders, cardiac and skeletal muscle toxicity, myelosuppression, neurotoxicity, and acute liver injury (mostly hepatic cytolysis) | Currently unknown | Possible involvement of ER stress in paclitaxel‐induced neurotoxicity |
| Protease inhibitors (e.g., indinavir and ritonavir) | Antiretroviral | GI toxicity, rash, kidney injury, hepatotoxicity (including cytolysis, cholestasis, and steatosis), dyslipidemia, lipodystrophy, insulin resistance, and type 2 diabetes | Possible involvement of proteasome inhibition and oxidative stress | Significant ER stress has been showed with atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, but not with amprenavir, darunavir, and tipranavir |
| Sertraline | Antidepressant (selective serotonin reuptake inhibitor) | Somnolence, GI disorders, tremor, sexual dysfunction, weight gain, and liver injury | Currently unknown. Possible role of mitogen‐activated protein kinase (MAPK) pathway activation | Possible involvement of ER stress in sertraline‐induced hepatotoxicity |
| Thapsigargin | Sesquiterpene lactone isolated from the plant Thapsia garganica, which has long been used in traditional Arabian medicine | Severe skin irritation, salivary hypersecretion, gastroenteritis, nervous disorders, and death | Inhibition of SERCA, thus leading to severe calcium depletion in the ER | Prototypical inducer of ER stress. In addition to ER stress, increase in free cytosolic calcium is inducing apoptosis in different types of cells treated with thapsigargin |
| Troglitazone | Antidiabetic (via activation of PPARγ) | Severe and fatal liver injury leading to the withdrawal of troglitazone from the market | Currently unknown. Possible role of mitogen‐activated protein kinase (MAPK) pathway activation | Possible involvement in troglitazone‐induced liver injury in addition with mitochondrial dysfunction and oxidative stress |
| Tunicamycin | Antibiotic active against different bacteria, fungi, and viruses | Major neurotoxicity and death in animals. Kidney and liver lesions are also observed in the treated animals | Impairment of glycosylation of newly synthesized proteins in the ER leading to the disruption of their folding | Prototypical inducer of ER stress. Tunicamycin has never been used in human medicine due to its toxicity |
| Zidovudine (AZT) | Antiretroviral (nucleoside reverse transcriptase inhibitor) | Lactic acidosis, myopathy, and hepatotoxicity (including cytolysis and steatosis) | Currently unknown. Possible impairment of proteasome activity | Although ER stress could be involved in steatosis, the current knowledge points to a major role of mitochondrial dysfunction in fat accretion induced by zidovudine |
ER, endoplasmic reticulum; CYPs, cytochromes P450; GI, gastrointestinal; PDI, protein disulfide isomerase; NAPQI, N‐acetyl‐p‐benzoquinone imine; NSAID, nonsteroidal anti‐inflammatory drug; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; PPARγ, peroxisome proliferator‐activated receptor‐γ.