Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma

Xipell, Enric; González-Huárriz, Marisol; Irujo, J. J. Martinez De; García-Garzón, Antonia; Lang, F.; Jiang, Hong; Fueyo, Juan; Gomez-Manzano, Candelaria; Alonso, Marta M.

doi:10.18632/oncotarget.8905

Cited by 59 publications

(56 citation statements)

References 49 publications

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“…ER is a key organelle with protein processing, intracellular calcium storage, as well as signaling regulation functions in eukaryotic cells (31). Although the anticancer effects of salinomycin have been established in a variety of preclinical studies using many different cancer types, there are few studies on the effects of salinomycin on glioma cancer cells (6). In the present study, salinomycin showed potent cytotoxic and apoptotic effects in human glioma U87MG cells.…”

Section: Discussionmentioning

confidence: 59%

“…Anticancer compounds may affect cellular redox reactions through accumulation of intracellular ROS (28,29), which in turn induce apoptosis and autophagy (30). Accumulating evidence indicates that apoptosis is also regulated by ER stress (6,21). ER is a key organelle with protein processing, intracellular calcium storage, as well as signaling regulation functions in eukaryotic cells (31).…”

Section: Discussionmentioning

confidence: 99%

“…The misfolded proteins induced ER stress to restore protein homeostasis and apoptotic cell death ensues when the stress is prolonged. Recent research revealed that apoptosis is induced via stimulation of ER stress in glioma cells (6,21). To investigate the ER stress pathway involved in salinomycin-induced apoptosis, we examined the expression levels of ER stress-related proteins (Ire1α, Bip and CHOP) by western blot analysis.…”

Section: Salinomycin Induces Er Stress-mediated Apoptosis In U87mgmentioning

confidence: 99%

“…Recent studies have shown that salinomycin displays potent antitumor activities in different types of cancer cells, including colorectal cancer (1), hepatocellular carcinoma (2), endometrial (3) and prostate cancer (4), and osteosacoma cells (5). However, there are few studies on its effect on glioma cancer cells (6). Gliomas are the most primary prevalent and aggressive form of intracranial tumors affecting adults 40-60 years of age (7,8).…”

Section: Introductionmentioning

confidence: 99%

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Salinomycin induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells

Kim

et al. 2017

Oncology Reports

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Abstract. Salinomycin is a polyether ionophore antibiotic that has recently been shown to induce cell apoptosis in human cancer cells displaying multiple mechanisms of drug resistance. In the present study, we explored the impact of salinomycin on the apoptosis and autophagy as well as the correlation between those effects and endoplasmic reticulum (ER) stress molecular mechanisms in human glioma U87MG cells. Apoptosis, autophagy and reactive oxygen species (ROS) were analyzed using flow cytometry. In addition, expression levels of apoptosis-, autophagy-and ER stress-related proteins were determined by western blotting. The results showed that salinomycin induced apoptosis, ER stress and autophagy in glioma cancer cell lines. In addition, salinomycin also induced ROS generation, and the ROS scavenger N-acetyl-L-cysteine was found to inhibit the salinomycin-induced apoptosis, ER stress and autophagy. The inhibition of ER stress with 4-phenylbutyric acid depressed salinomycin-induced apoptosis and autophagy. Salinomycin increased the expression of autophagy marker protein, LC3B, and accumulation of acidic vesicular organelles. Furthermore, pre-treatment with the autophagy inhibitor 3-methyladenine showed potential in increasing the apoptosis rate induced by salinomycin in the U87MG cells. Taken together, these results revealed that salinomycin induced apoptosis and autophagy via ER stress mediated by ROS, suggesting that ER stress by salinomycin plays a dual function in both promoting and suppressing cell death.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Salinomycin Induces Er Stress-mediated Apoptosis In U87mgmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Salinomycin induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells

Kim

et al. 2017

Oncology Reports

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“…Besides, it has been reported that salinomycin, another polyether ionophore, can inhibit autophagic flux in hepatocellular carcinoma cells and breast cancer stem-like/progenitor cells (Klose, Stankov, Kleine, Ramackers, Panayotova-Dimitrova, Jager, Klempnauer, Winkler, Bektas, Behrens and Vondran 2014, Yue, Hamai, Tonelli, Bauvy, Nicolas, Tharinger, Codogno and Mehrpour 2013). Particularly, salinomycin has been found to suppress autophagic flux, triggering necrosis in glioblastoma cells (Xipell, Gonzalez-Huarriz, Martinez de Irujo, Garcia-Garzon, Lang, Jiang, Fueyo, Gomez-Manzano and Alonso 2016). Here, we found that maduramicin also blocked autophagic flux with accumulation of both LC3-II and p62/SQSTM1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Maduramicin induces apoptosis and necrosis, and blocks autophagic flux in myocardial H9c2 cells

Chen

Jiang

et al. 2017

J of Applied Toxicology

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Maduramicin, a polyether ionophore antibiotic, is widely used as an anticoccidial agent in the poultry industry. It has been reported that maduramicin may cause heart and skeletal muscle cell damage, resulting in heart failure, skeletal muscle degeneration and even death in animals and humans, if improperly used. However, the molecular mechanism behind its capability to cause death of cardiac cells is not known. Here, we show that maduramicin induced apoptosis and necrosis in rat myocardial cells (H9c2). Maduramicin did not apparently upregulate the expression of pro-apoptotic proteins (e.g., BAD, BAK and BAX) or downregulate the expression of anti-apoptotic proteins (e.g. Bcl-2, Bcl-xL, Mcl-1 and survivin). Interestingly, maduramicin increased the expression of DR4 and TRAIL, activating caspases 8/3 and triggering cleavage of poly ADP ribose polymerase (PARP). In addition, maduramicin induced nuclear translocation of apoptosis inducing factor. Furthermore, maduramicin blocked autophagic flux, as evidenced by inducing accumulation of both LC3-II and p62/SQSTM1. Taken together, the above results suggest that maduramicin executes its toxicity in the myocardial cells at least by inducing caspase-dependent cell death through TRAIL/DR4-mediated extrinsic pathway and caspase-independent cell death by inducing apoptosis inducing factor nuclear translocation and blocking autophagic flux. Our findings provide a new insight into the molecular mechanism of maduramicin's toxicity in myocardial cells.

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Spheroid‐based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma

Perut

Sbrana

Avnet

et al. 2018

Journal Orthopaedic Research

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Chondrosarcoma (CS) is a cartilage malignancy of adulthood that is treated by surgery alone, since chemotherapy is considered ineffective. Unfortunately, a large proportion of patients with CS develop lung metastases, and several die of the disease. In this study, we compared 3D-spheroid cultures and conventional cell monolayer models in order to identify the best way to select anticancer agents that could be effective for the systemic control of CS. Using SW1353 cells, we developed a three-dimensional (3D) in vitro culture model to mimic in vivo features of CS microenvironment and evaluated the efficacy of different drugs to modulate CS cell proliferation and survival in 2D versus 3D-cultures. Doxorubicin (DXR) and cisplatin, that are widely employed in sarcomas, were less effective on 3D-CS spheroids when compared to standard monolayer models, whereas treatment with the ionophore salinomycin (SAL) had a strong cytotoxic effect both on 2D and 3D-cultures. Furthermore, as demonstrated by the reduced viability and the enhanced DXR nuclear localization, SAL enhanced DXR cytotoxicity in 3D-CS spheroids also at sub-lethal doses. SAL activity on 3D-CS spheroids was mediated by a significant induction of apoptosis via caspase activation. This study demonstrates that preclinical tests significantly differ in monolayer and 3D cultures of CS cells. Using this approach, SAL, alone or, at sub-lethal concentrations, in combination with DXR, represents a promising agent for the systemic treatment of CS. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

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Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma

Cited by 59 publications

References 49 publications

Salinomycin induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells

Salinomycin induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells

Maduramicin induces apoptosis and necrosis, and blocks autophagic flux in myocardial H9c2 cells

Spheroid‐based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma

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