A by-product of glutathione production in cancer cells may cause disruption in bone metabolic processesThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

2010 ◽  
Vol 88 (3) ◽  
pp. 197-203 ◽  
Author(s):  
Eric P. Seidlitz ◽  
Mohit K. Sharma ◽  
Gurmit Singh
Keyword(s):  
Oxidative Stress ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Metabolic Response ◽  
Glutamate Release ◽  
Waste Product ◽  
Cell Types ◽  
Redox Balance ◽  
Bone Homeostasis ◽  
Sensitive Organ

Bone is a frequent site for metastasis of breast and prostate cancers, often resulting in pathologic changes in bone metabolism and severe pain. The mechanisms involved are not well understood, but tumour cells may release factors that interfere with bone homeostasis. Several observations have led us to hypothesize that the functional disruptions in bone metastasis are the result of a biological process common to many cell types. The high metabolic activity characteristic of cancer cells often upregulates oxidative stress protection mechanisms such as the antioxidant molecule glutathione. In maintaining redox balance, this normal metabolic response may result in unintended pathologic effects in certain sensitive organ sites. Malignant glioma cells kill surrounding neurons in the brain specifically by secreting the amino acid glutamate, an obligatory waste product of glutathione synthesis. We suggest that glutamate release is a plausible mechanism that may account for the pathologic changes in bone metastasis, since bone, like brain, is also highly sensitive to glutamatergic disruption. This report reviews the available evidence to draw a mechanistic connection between tumour cell oxidative stress and the pathology seen in patients with bone metastasis.

scholarly journals Osteosarcoma and Metastasis Associated Bone Degradation—A Tale of Osteoclast and Malignant Cell Cooperativity

2021 ◽  
Vol 22 (13) ◽  
pp. 6865
Author(s):  
Kirstine Sandal Nørregaard ◽  
Henrik Jessen Jürgensen ◽  
Henrik Gårdsvoll ◽  
Lars Henning Engelholm ◽  
Niels Behrendt ◽  
...  
Keyword(s):  
Bone Metastasis ◽  
Cancer Cells ◽  
Bone Cancer ◽  
Degradation Process ◽  
Cell Types ◽  
Malignant Cell ◽  
Pathological Process ◽  
Course Of Disease ◽  
Bone Degradation ◽  
Primary Bone

Cancer-induced bone degradation is part of the pathological process associated with both primary bone cancers, such as osteosarcoma, and bone metastases originating from, e.g., breast, prostate, and colon carcinomas. Typically, this includes a cancer-dependent hijacking of processes also occurring during physiological bone remodeling, including osteoclast-mediated disruption of the inorganic bone component and collagenolysis. Extensive research has revealed the significance of osteoclast-mediated bone resorption throughout the course of disease for both primary and secondary bone cancer. Nevertheless, cancer cells representing both primary bone cancer and bone metastasis have also been implicated directly in bone degradation. We will present and discuss observations on the contribution of osteoclasts and cancer cells in cancer-associated bone degradation and reciprocal modulatory actions between these cells. The focus of this review is osteosarcoma, but we will also include relevant observations from studies of bone metastasis. Additionally, we propose a model for cancer-associated bone degradation that involves a collaboration between osteoclasts and cancer cells and in which both cell types may directly participate in the degradation process.

Oxidative stress and cancer pain

2013 ◽  
Vol 91 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Robert G. Ungard ◽  
Eric P. Seidlitz ◽  
Gurmit Singh
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Cellular Response ◽  
Bone Pain ◽  
Glutamate Release ◽  
Bone Cell ◽  
Common Source ◽  
Pathological Feature ◽  
Breast Cancers ◽  
Current Standard

Breast cancers are the most common source of metastases to bone, of which cancer-induced bone pain is a frequent pathological feature. Cancer-induced bone pain is a unique pain state with multiple determinants that remains to be well understood and managed. Current standard treatments are limited by dose-dependent side effects that can reduce the quality of life of patients. Glutamate is a neurotransmitter and bone cell-signalling molecule that is released via the system [Formula: see text] cystine/glutamate antiporter from cancer cell types that frequently metastasize to bone, including breast cancers. In cancer cells, glutamate release is understood to be a side effect of the cellular response to oxidative stress that upregulates the expression and activity of system [Formula: see text] to promote the increased import of cystine. Attenuation of glutamate release from cancer cells has been demonstrated to result in reductions in associated cancer-induced bone pain in animal models. This review examines the clinical implications of attenuating cystine uptake and glutamate release in the treatment of cancer-induced bone pain.

scholarly journals Tuning cell behavior with nanoparticle shape

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0240197
Author(s):  
Edoardo Scarpa ◽  
Cesare De Pace ◽  
Adrian Steve Joseph ◽  
Senio Campos de Souza ◽  
Alessandro Poma ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Metabolic Response ◽  
Biomedical Application ◽  
Gradient Centrifugation ◽  
Cell Types ◽  
Cell Behavior ◽  
Geometrical Structures ◽  
Nanoparticle Shape ◽  
Kinetics Of Uptake ◽  
Replication Activity

We investigated how the shape of polymeric vesicles, made by the exact same material, impacts the replication activity and metabolic state of both cancer and non-cancer cell types. First, we isolated discrete geometrical structures (spheres and tubes) from a heterogeneous sample using density-gradient centrifugation. Then, we characterized the cellular internalization and the kinetics of uptake of both types of polymersomes in different cell types (either cancer or non-cancer cells). We also investigated the cellular metabolic response as a function of the shape of the structures internalized and discovered that tubular vesicles induce a significant decrease in the replication activity of cancer cells compared to spherical vesicles. We related this effect to the significant up-regulation of the tumor suppressor genes p21 and p53 with a concomitant activation of caspase 3/7. Finally, we demonstrated that combining the intrinsic shape-dependent effects of tubes with the delivery of doxorubicin significantly increases the cytotoxicity of the system. Our results illustrate how the geometrical conformation of nanoparticles could impact cell behavior and how this could be tuned to create novel drug delivery systems tailored to specific biomedical application.

Coordination of Fenretinide-Induced Apoptosis by Stress-Responsive Regulators in Leukemia Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4730-4730
Author(s):  
Kankan Wang ◽  
Hai Fang ◽  
Da-Kai Xiao ◽  
Xue-Hua Zhu ◽  
Miao- Miao He ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Target Genes ◽  
Systems Approach ◽  
Transcriptome Profiling ◽  
Redox Balance ◽  
Pharmacological Intervention ◽  
Downstream Effects ◽  
Induced Apoptosis

Abstract Pharmacological intervention affecting intracellular redox balance often results in oxidative stress-mediated apoptosis, which also represents a new direction for cancer therapeutic designs. However, mechanistic links between redox signals and their downstream effects on apoptosis have not yet been elucidated in cancer cells. Here, we report a detailed analysis of fenretinide-induced apoptosis in leukemia-derived cells through a systems approach, integrating experimental and computational methods together with advanced data mining tools. Robust transcriptome profiling reveals numerous stress-responsive events at the temporal and spatial levels, including oxidative stress, endoplasmic reticulum stress/unfolded protein response, translational repression, proteasome activation, and apoptosis induction. Moreover, stress-responsive transcription factors, as highlighted by NRF2 and HSF1, play prominent roles in the configuration of these relevant events. Several lines of evidence suggest that these stress-responsive regulators and thus their target genes are involved not only in converting oxidative signaling into downstream effects but also in coordinating the progression of cell apoptosis. This study provides a roadmap for understanding oxidative stress-mediated apoptosis in cancer cells, which may be further developed into more sophisticated therapeutic protocols, as implicated by synergistic induction of cell apoptosis using proteasome inhibitors with fenretinide.

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

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1188
Author(s):  
Jinthe Van Loenhout ◽  
Marc Peeters ◽  
Annemie Bogaerts ◽  
Evelien Smits ◽  
Christophe Deben
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Treatment Strategies ◽  
Redox Balance ◽  
Cellular Responses ◽  
Anticancer Therapy ◽  
Treatment Modalities ◽  
Oxygen Species ◽  
Novel Target ◽  
High Level

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.

scholarly journals The Phytochemical Indicaxanthin Synergistically Enhances Cisplatin-Induced Apoptosis in HeLa Cells via Oxidative Stress-Dependent p53/p21waf1 Axis

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 994
Author(s):  
Mario Allegra ◽  
Antonella D’Anneo ◽  
Anna Frazzitta ◽  
Ignazio Restivo ◽  
Maria Antonia Livrea ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cycle ◽  
Cell Viability ◽  
Cancer Cells ◽  
Morphological Changes ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Redox Balance ◽  
Individual Treatment ◽  
Stress Dependent

Combining phytochemicals with chemotherapics is an emerging strategy to treat cancer to overcome drug toxicity and resistance with natural compounds. We assessed the effects of indicaxanthin (Ind), a pigment obtained from Opuntia ficus-indica (L. Mill) fruit, combined with cisplatin (CDDP) against cervical cancer cells (HeLa). Measured cell viability via Trypan blue assay; cell morphology via fluorescence microscopy; apoptosis, cell cycle, mitochondrial membrane potential (MMP) and cell redox balance via flow-cytometry; expression levels of apoptosis-related proteins via western blot. Cell viability assays and Chou-Talalay plot demonstrated that the combination of CDDP and Ind had synergistic cytotoxic effects. Combined treatment had significant effects (p < 0.05) on phosphatidylserine externalization, cell morphological changes, cell cycle arrest, fall in MMP, ROS production and GSH decay compared with the individual treatment groups. Bax, cytochrome c, p53 and p21waf1 were over-expressed, while Bcl-2 was downregulated. Pre-treatment with N-acetyl-l-cysteine abolished the observed synergistic effects. We also demonstrated potentiation of CDDP anticancer activity by nutritionally relevant concentrations of Ind. Oxidative stress-dependent mitochondrial cell death is the basis of the chemosensitizing effect of Ind combined with CDDP against HeLa cancer cells. ROS act as upstream signaling molecules to initiate apoptosis via p53/p21waf1 axis. Ind can be a phytochemical of interest in combo-therapy.

scholarly journals Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 510
Author(s):  
Maria Letizia Taddei ◽  
Laura Pietrovito ◽  
Angela Leo ◽  
Paola Chiarugi
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Environmental Changes ◽  
Malignant Tumors ◽  
Waste Product ◽  
Tumor Stroma ◽  
Cell Types ◽  
Extracellular Proteins ◽  
Strong Acidity ◽  
Current Therapies

Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

scholarly journals Hepatic ZIP8 deficiency is associated with disrupted selenium homeostasis, liver pathology, and tumor formation

2018 ◽  
Vol 315 (4) ◽  
pp. G569-G579 ◽  
Author(s):  
Liu Liu ◽  
Xiangrong Geng ◽  
Yihong Cai ◽  
Bryan Copple ◽  
Masafumi Yoshinaga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inductively Coupled Plasma ◽  
Normal Liver ◽  
Cell Types ◽  
Redox Balance ◽  
Hepatic Function ◽  
Tumor Formation ◽  
Membrane Transporter ◽  
Liver Pathology ◽  
Hepatocellular Injury

Zrt/Irt-like protein 8 (ZIP8) (encoded by Slc39a8) is a multifunctional membrane transporter that influxes essential metal cations Zn2+, Mn2+, Fe2+, and nonmetal inorganic selenite (HSeO3−). Physiological roles of ZIP8 in different cell types and tissues remain to be elucidated. We aimed to investigate ZIP8 functions in liver. Two mouse models were used in this study: 1) 13- to 21-mo-old Slc39a8(+/neo) hypomorphs having diminished ZIP8 levels and 2) a liver-specific ZIP8 acute knockdown mouse (Ad-shZip8). Histology, immunohistochemistry, and Western blotting were used to investigate ZIP8-deficiency effects on hepatic injury, inflammatory changes, and oxidative stress. Selenium (Se) and zinc (Zn) were quantified in tissues by inductively coupled plasma-mass spectrophotometry. We found that ZIP8 is required to maintain normal liver function; moderate or acute decreases in ZIP8 activity resulted in hepatic pathology. Spontaneous liver neoplastic nodules appeared in ~50% of Slc39a8(+/neo) between 13 and 21 mo of age, exhibiting features of inflammation, fibrosis, and liver injury. In Ad-shZip8 mice, significant hepatomegaly was observed; histology showed ZIP8 deficiency was associated with hepatocyte injury, inflammation, and proliferation. Significant decreases in Se, but not Zn, were found in Ad-shZip8 liver. Consistent with this Se deficit, liver expression of selenoproteins glutathione peroxidases 1 and 2 was downregulated, along with decreases in antioxidant superoxide dismutases 1 and 2, consistent with increased oxidative stress. Thus, ZIP8 plays an important role in maintaining normal hepatic function, likely through regulating Se homeostasis and redox balance. Hepatic ZIP8 deficiency is associated with liver pathology, including oxidative stress, inflammation, proliferation, and hepatocellular injury. NEW & NOTEWORTHY Zrt/Irt-like protein 8 (ZIP8) is a multifunctional membrane transporter that facilitates biometal and mineral uptake. The role of ZIP8 in liver physiology has not been previously investigated. Liu et al. discovered unique ZIP8 functions, i.e., regulation of hepatic selenium content and association of ZIP8 deficiency in mouse liver with liver defects.

scholarly journals Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Lingyan Zhang ◽  
Jian Zhang ◽  
Yuanqing Jin ◽  
Gang Yao ◽  
Hai Zhao ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Lipid Peroxide ◽  
Cell Types ◽  
Redox Balance ◽  
Antioxidant Genes ◽  
Cellular Iron

Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.

scholarly journals Understanding of ROS-Inducing Strategy in Anticancer Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Su Ji Kim ◽  
Hyun Soo Kim ◽  
Young Rok Seo
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Anticancer Drugs ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Biological Response ◽  
Buthionine Sulfoximine ◽  
Redox Balance ◽  
Anticancer Therapy ◽  
Therapeutic Effects

Redox homeostasis is essential for the maintenance of diverse cellular processes. Cancer cells have higher levels of reactive oxygen species (ROS) than normal cells as a result of hypermetabolism, but the redox balance is maintained in cancer cells due to their marked antioxidant capacity. Recently, anticancer therapies that induce oxidative stress by increasing ROS and/or inhibiting antioxidant processes have received significant attention. The acceleration of accumulative ROS disrupts redox homeostasis and causes severe damage in cancer cells. In this review, we describe ROS-inducing cancer therapy and the anticancer mechanism employed by prooxidative agents. To understand the comprehensive biological response to certain prooxidative anticancer drugs such as 2-methoxyestradiol, buthionine sulfoximine, cisplatin, doxorubicin, imexon, and motexafin gadolinium, we propose and visualize the drug-gene, drug-cell process, and drug-disease interactions involved in oxidative stress induction and antioxidant process inhibition as well as specific side effects of these drugs using pathway analysis with a big data-based text-mining approach. Our review will be helpful to improve the therapeutic effects of anticancer drugs by providing information about biological changes that occur in response to prooxidants. For future directions, there is still a need for pharmacogenomic studies on prooxidative agents as well as the molecular mechanisms underlying the effects of the prooxidants and/or antioxidant-inhibitor agents for effective anticancer therapy through selective killing of cancer cells.

Sign in / Sign up

Export Citation Format

Share Document