Inhibition of glutathione metabolism attenuates esophageal cancer progression

Peng, Liang; Linghu, Ruixia; Chen, Demeng; Yang, Jing; Kou, Xiaoxue; Wang, Xiangzhen; Hu, Yi; Jiang, Yi‐Zhou; Yang, Junlan

doi:10.1038/emm.2017.15

Cited by 17 publications

(16 citation statements)

References 32 publications

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“…Therefore, one might consider exploring different routes of BSO administration to avoid an invasive procedure and the risk of inducing a potentially fatal haemorrhage in highly vascularized tumours. An efficient reduction of tumour burden has, for instance, been shown in an animal model of oesophageal cancer, where BSO was dissolved in drinking water at a concentration of 20 mM [ 55 ]. In an orthotopic glioma model, a reduction of tumour glutathione to about 8% of the non-treated control values was achieved by a combination of intraperitoneal and oral BSO administration [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…The results of at least two Phase I clinical trials in which BSO was administered intravenously as adjuvant therapy in patients with solid malignant tumours have been published [ 55 , 56 ]. An intracellular GSH depletion to about 30–40% of the baseline levels was induced, resulting in a significant inhibition of y-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

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Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project

et al. 2018

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BackgroundResistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time.MethodsBSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease.The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy.Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31.ResultsAfter tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain.ConclusionsIn this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project

et al. 2018

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“…The dosage of Ori was comparative to our experiment, specifically, Ori (27 μM) significantly reduced GSH in esophageal cancer TE1 cells. Importantly, Peng et al showed that glutathione metabolism was among the top enriched pathways in ESCC (Esophageal squamous cell carcinoma) through studies on ESCC mice, suggesting that inhibition of glutathione metabolism may be an effective strategy for ESCC therapy (Peng, Linghu, & Chen, 2017). As mentioned before, lipid peroxidation is the essential feature of ferroptosis, thus dysregulation of GSH synthesis and metabolism would like to induce ferroptosis in ESCC.…”

Section: Discussionmentioning

confidence: 99%

“…All values presented as mean ± SD (n = 3 for each group). Statistical differences were calculated by one-way ANOVA: ***p < .001; **p < .01 vs. 0 hr group [Colour figure can be viewed at wileyonlinelibrary.com] inhibition of glutathione metabolism may be an effective strategy for ESCC therapy (Peng, Linghu, & Chen, 2017). As mentioned before, lipid peroxidation is the essential feature of ferroptosis, thus dysregulation of GSH synthesis and metabolism would like to induce ferroptosis in ESCC.…”

Section: Discussionmentioning

confidence: 99%

Oridonin induces ferroptosis by inhibiting gamma‐glutamyl cycle in TE1 cells

Zhang

Wang

Zhou

et al. 2020

Phytotherapy Research

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Oridonin (Ori) is a natural tetracyclic diterpenoid active compound with excellent antitumor activity, but the mechanism of Ori on esophageal cancer cell, TE1, remains unclear. In this study, we examined the levels of intracellular iron, malondialdehyde, and reactive oxygen species after Ori treatment, while interfering with the effects of Ori with ferroptosis inhibitor, demonstrating that Ori's inhibition of TE1 cell proliferation is associated with ferroptosis. To understand the molecular mechanism of Ori, we performed UPLC–MS/MS metabolomics profiling on TE1 cells, which show that gamma‐glutamyl amino acids (gamma‐glutamylleucine, gamma‐glutamylvaline), 5‐oxoproline, glutamate, GSH, and GSSG are changed significantly after Ori treatment. Meanwhile, the activity of gamma‐glutamyl transpeptidase 1 (GGT1) decreased. This revealed that Ori inhibited the gamma‐glutamyl cycle in TE1 cells. Furthermore, we found that Ori can covalently bind to cysteine to form the conjugate oridonin‐cysteine (Ori‐Cys), resulting in the inhibition of glutathione synthesis, which is consistent with the decrease in the enzymatic activity of glutamate cysteine ligase catalytic subunit (GCLC). Eventually, the value of intracellular GSH/GSSG was reduced, and the enzymatic activity of the glutathione peroxidase 4 (GPX4) was significantly decreased. In conclusion, our experiments indicated that Ori can inhibit the gamma‐glutamyl cycle, thereby inducing ferroptosis to exert anti‐cancer activity.

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“…For example, auranofin has shown to decrease the expression of NF-kB, thereby overcoming acquired therapy resistance [70,71]. Similar effects were obtained when inhibiting GSH metabolism [72]. However, it should be mentioned that the activation of NF-kB is also responsible for inflammatory responses, which can induce cross-presentation of tumor antigens and stimulate antitumor immune responses [73].…”

Section: Combinations Of Different Oxidative Stress-inducing Therapiesmentioning

confidence: 90%

Oxidative Stress-Inducing Anticancer Therapies: Taking a Closer Look at Their Immunomodulating Effects

et al. 2020

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Cancer cells are characterized by higher levels of reactive oxygen species (ROS) compared to normal cells as a result of an imbalance between oxidants and antioxidants. However, cancer cells maintain their redox balance due to their high antioxidant capacity. Recently, a high level of oxidative stress is considered a novel target for anticancer therapy. This can be induced by increasing exogenous ROS and/or inhibiting the endogenous protective antioxidant system. Additionally, the immune system has been shown to be a significant ally in the fight against cancer. Since ROS levels are important to modulate the antitumor immune response, it is essential to consider the effects of oxidative stress-inducing treatments on this response. In this review, we provide an overview of the mechanistic cellular responses of cancer cells towards exogenous and endogenous ROS-inducing treatments, as well as the indirect and direct antitumoral immune effects, which can be both immunostimulatory and/or immunosuppressive. For future perspectives, there is a clear need for comprehensive investigations of different oxidative stress-inducing treatment strategies and their specific immunomodulating effects, since the effects cannot be generalized over different treatment modalities. It is essential to elucidate all these underlying immune effects to make oxidative stress-inducing treatments effective anticancer therapy.

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Inhibition of glutathione metabolism attenuates esophageal cancer progression

Cited by 17 publications

References 32 publications

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project

Oridonin induces ferroptosis by inhibiting gamma‐glutamyl cycle in TE1 cells

Oxidative Stress-Inducing Anticancer Therapies: Taking a Closer Look at Their Immunomodulating Effects

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