Oridonin induces oxidative stress-mediated cancer cells apoptosis via targeting thioredoxin reductase

2021 ◽  
Vol 23 ◽  
Author(s):  
Dongzhu Duan ◽  
Xiaolu Feng ◽  
Dabo Pan ◽  
Le Wang ◽  
Yanru Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Malignant Tumors ◽  
Thioredoxin Reductase ◽  
Reactive Oxygen ◽  
Annexin V ◽  
Oxygen Species ◽  
Reduction Assay

Background: Thioredoxin reductase (TrxR) plays vital role in regulating cellular redox balance as well as redox-mediated signal transduction. Accumulating evidence supports that overactivation of TrxR is closely related to tumorigenesis and that targeting TrxR ablation reverses the growth of numerous malignant tumors, making TrxR a promising target for cancer chemotherapy. Thus, the discovery and development of molecules as promising anticancer agents that target TrxR is of great significance. Oridonin was shown to inhibit TrxR activity, but the detailed cellular mechanism is largely unknown. Objective: The study investigated the mechanism of action and underlying inhibitory properties of oridonin on TrxR in HeLa cells. Methods: A covalent docking was performed to reveal the possible interaction between oridonin and TrxR by Schrödinger Software Suite. TrxR activity was determined by 5,5’-dithiobis-2-nitrobenzoic acid reduction assay and endpoint insulin reduction assay. Sulforhodamine B and colony formation assay were employed to assess the viability and growth of cells. Reactive oxygen species level was measured by probe 2’, 7’-dichlorfluorescein diacetate, and dihydroethidium. Hoechst 33342 staining, caspase 3 activation, and fluorescein-5-isothiocyanate-conjugated Annexin V and propidium iodide double staining were used to evaluate apoptosis. Results: Here, we reported the oridonin as a potent inhibitor of TrxR. Inhibition of TrxR results in a decrease of thiols content and total glutathione elevates reactive oxygen species levels, and finally promotes oxidative stress-mediated apoptosis of cancer cells. Conclusion : Targeting TrxR by oridonin discloses a novel molecular mechanism underlying the biological action of oridonin and sheds light on developing oridonin as a potential tumor therapeutic agent.

scholarly journals Protocatechuic Acid, a Simple Plant Secondary Metabolite, Induced Apoptosis by Promoting Oxidative Stress through HO-1 Downregulation and p21 Upregulation in Colon Cancer Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1485
Author(s):  
Rosaria Acquaviva ◽  
Barbara Tomasello ◽  
Claudia Di Giacomo ◽  
Rosa Santangelo ◽  
Alfonsina La Mantia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Reactive Oxygen Species ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Protocatechuic Acid ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Colon Cancer Cells ◽  
Glutamylcysteine Synthetase

Gastrointestinal cancers, particularly colorectal cancer, are mainly influenced by the dietary factor. A diet rich in fruits and vegetables can help to reduce the incidence of colorectal cancer thanks to the phenolic compounds, which possess antimutagenic and anticarcinogenic properties. Polyphenols, alongside their well-known antioxidant properties, also show a pro-oxidative potential, which makes it possible to sensitize tumor cells to oxidative stress. HO-1 combined with antioxidant activity, when overexpressed in cancer cells, is involved in tumor progression, and its inhibition is considered a feasible therapeutic strategy in cancer treatment. In this study, the effects of protocatechuic acid (PCA) on the viability of colon cancer cells (CaCo-2), annexin V, LDH release, reactive oxygen species levels, total thiol content, HO-1, γ-glutamylcysteine synthetase, and p21 expression were evaluated. PCA induced, in a dose-dependent manner, a significantly reduced cell viability of CaCo-2 by oxidative/antioxidant imbalance. The phenolic acid induced modifications in levels of HO-1, non-proteic thiol groups, γ-glutamylcysteine synthetase, reactive oxygen species, and p21. PCA induced a pro-oxidant effect in cancer cells, and the in vitro pro-apoptotic effect on CaCo-2 cells is mediated by the modulation of redox balance and the inhibition of the HO-1 system that led to the activation of p21. Our results suggest that PCA may represent a useful tool in prevention and/or therapy of colon cancer.

scholarly journals Positive feedback between ROS and cis-axis of PIASxα/p38α-SUMOylation/MK2 facilitates gastric cancer metastasis

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Qian Wang ◽  
Ci Xu ◽  
Qiang Fan ◽  
Haihua Yuan ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gastric Cancer ◽  
Reactive Oxygen Species ◽  
Stress Response ◽  
Cancer Cells ◽  
Regulatory Mechanism ◽  
Reactive Oxygen ◽  
Oxidative Stress Response ◽  
Oxygen Species ◽  
Gastric Cancer Cells

AbstractMAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.

scholarly journals Unifying Mechanism for Nutrients as Anticancer Agents: Electron Transfer, Reactive Oxygen Species and Oxidative Stress

2017 ◽  
Vol 9 (8) ◽  
pp. 66 ◽  
Author(s):  
Peter Kovacic ◽  
Ratnasamy Somanathan
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Electron Transfer ◽  
Anticancer Agents ◽  
Mode Of Action ◽  
Recent Article ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Bactericidal Action ◽  
And Oxidative Stress

A recent article deals with various nutrients in relation to bactericidal action. The present article focuses on a unifying mode of action for the nutrients, namely, resveratrol, epigallocatechin, polyene-ß-carotene, polyene lycopene, piperine, curcumin, genistein, luteolin, sulforaphane and pomegranate extract. The mechanism is based on electron transfer, reactive oxygen species and oxidative stress, which comprises an extension of earlier reports involving agents. Most of the compounds are precursors of electron transfer quinones, whereas others fit into the polyene category. The nutrients are better known as antioxidants. The dichotomy is addressed.

scholarly journals Dose-Dependent Effects of Cold Atmospheric Argon Plasma on the Mesenchymal Stem and Osteosarcoma Cells In Vitro

2021 ◽  
Vol 22 (13) ◽  
pp. 6797
Author(s):  
Artem M. Ermakov ◽  
Olga N. Ermakova ◽  
Vera A. Afanasyeva ◽  
Anton L. Popov
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Stem Cells ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
Argon Plasma ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Normal Cells

The antimicrobial, anti-inflammatory and tissue-stimulating effects of cold argon atmospheric plasma (CAAP) accelerate its use in various fields of medicine. Here, we investigated the effects of CAAP at different radiation doses on mesenchymal stem cells (MSCs) and human osteosarcoma (MNNG/HOS) cells. We observed an increase in the growth rate of MSCs at sufficiently low irradiation doses (10–15 min) of CAAP, while the growth of MNNG/HOS cells was slowed down to 41% at the same irradiation doses. Using flow cytometry, we found that these effects are associated with cell cycle arrest and extended death of cancer cells by necrosis. Reactive oxygen species (ROS) formation was detected in both types of cells after 15 min of CAAP treatment. Evaluation of the genes’ transcriptional activity showed that exposure to low doses of CAAP activates the expression of genes responsible for proliferation, DNA replication, and transition between phases of the cell cycle in MSCs. There was a decrease in the transcriptional activity of most of the studied genes in MNNG/HOS osteosarcoma cancer cells. However, increased transcription of osteogenic differentiation genes was observed in normal and cancer cells. The selective effects of low and high doses of CAAP treatment on cancer and normal cells that we found can be considered in terms of hormesis. The low dose of cold argon plasma irradiation stimulated the vital processes in stem cells due to the slight generation of reactive oxygen species. In cancer cells, the same doses evidently lead to the formation of oxidative stress, which was accompanied by a proliferation inhibition and cell death. The differences in the cancer and normal cells’ responses are probably due to different sensitivity to exogenous oxidative stress. Such a selective effect of CAAP action can be used in the combined therapy of oncological diseases such as skin neoplasms, or for the removal of remaining cancer cells after surgical removal of a tumor.

scholarly journals Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5252
Author(s):  
Yasuyoshi Miyata ◽  
Yuta Mukae ◽  
Junki Harada ◽  
Tsuyoshi Matsuda ◽  
Kensuke Mitsunari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Reactive Oxygen ◽  
Chemotherapeutic Agents ◽  
Malignant Neoplasms ◽  
Oxygen Species ◽  
Efficient Treatment ◽  
Intracellular Ros

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species (ROS). Accumulation of ROS occurs due to dysregulation of homeostasis in an otherwise strictly controlled physiological condition. In fact, intracellular ROS levels are closely associated with the pathological status and outcome of numerous diseases. Notably, mitochondria are recognized as the critical regulator and primary source of ROS. Damage to mitochondria increases mitochondrial ROS (mROS) production, which leads to an increased level of total intracellular ROS. However, intracellular ROS level may not always reflect mROS levels, as ROS is not only produced by mitochondria but also by other organelles such as endoplasmic reticulum and peroxisomes. Thus, an evaluation of mROS would help us to recognize the biological and pathological characteristics and predictive markers of malignant tumors and develop efficient treatment strategies. In this review, we describe the pathological significance of mROS in malignant neoplasms. In particular, we show the association of mROS-related signaling in the molecular mechanisms of chemically synthesized and natural chemotherapeutic agents and photodynamic therapy.

scholarly journals Parthenolide Induces Reactive Oxygen Species-Mediated Autophagic Cell Death in Human Osteosarcoma Cells

2016 ◽  
Vol 40 (1-2) ◽  
pp. 146-154 ◽  
Author(s):  
Chen Yang ◽  
Qing Ou Yang ◽  
Qing-Jie Kong ◽  
Wen Yuan ◽  
Yue-Ping Ou Yang
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cancer Cells ◽  
Reactive Oxygen ◽  
Annexin V ◽  
Pharmacological Action ◽  
Autophagic Cell Death ◽  
Oxygen Species ◽  
Human Osteosarcoma ◽  
Human Osteosarcoma Cells

Background and Aim: Osteosarcoma is a devastating tumor of bone, primarily affecting adolescents. Parthenolide, a naturally occurring small molecule that interferes with NF-κB signaling, has recently attracted considerable attention because of its pharmacological action involving anti-cancer effects. However, the mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. Methods: In this study, the effects of parthenolide were evaluated and characterized in human osteosarcoma cancer cell. Cell viability was assessed by CCK-8. Apoptosis was assessed by Annexin V-FITC/PI Flow cytometry assay. Relative quantitative real-time PCR and western blot were used to determine the expressions of genes and proteins. Results: Our results suggest that parthenolide did not cause caspase-dependent cell death in osteosarcoma cancer cells, as indicated by the absence of significant early apoptosis as well as caspase-3 cleavage. Instead, parthenolide increased the autophagy and mitophagy, as characterized by increased PINK1 and Parkin translocation to mitochondria and enhanced autophagy proteins. The induction of autophagy by parthenolide was associated with the increase of reactive oxygen species (ROS). ROS antioxidants N-acetylcysteine (NAC) attenuated parthenolide-induced autophagy activity. Conclusions: Our findings unveil a novel mechanism of drug action by parthenolide in osteosarcoma cancer cells and suggest a potential value of treating osteosarcoma cancer through a caspase-independent autophagic cell death by ROS activation.

Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation

2016 ◽  
Vol 45 (48) ◽  
pp. 19157-19171 ◽  
Author(s):  
Koushambi Mitra
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Light Exposure ◽  
Reactive Oxygen ◽  
Platinum Complexes ◽  
Oxygen Species

Platinum complexes can act as prodrugs which are non-cytotoxic in the dark but generate active platinum(ii) species and lethal reactive oxygen species on light exposure only in cancer cells, therefore leaving healthy cells unaffected.

Small-molecule anticancer agents kill cancer cells by harnessing reactive oxygen species in an iron-dependent manner

2018 ◽  
Vol 16 (9) ◽  
pp. 1465-1479 ◽  
Author(s):  
Sara R. Fedorka ◽  
Kevin So ◽  
Ayad A. Al-Hamashi ◽  
Ibtissam Gad ◽  
Ronit Shah ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Cells ◽  
Cell Lines ◽  
Small Molecule ◽  
Anticancer Agents ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Open Chain ◽  
New Class

In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species in an iron-dependent manner.

scholarly journals Breast Cancer Cell Lines, HER2/Neu Phenotype, and a Higher Propensity to Reactive Oxygen Species Production

2021 ◽  
pp. 137-142
Author(s):  
Zahra Mohammadi Abgarmi ◽  
Abbas Sahebghadam Lotfi ◽  
Saeid Abroun ◽  
Masoud Soleimani ◽  
Shahla Mohammad Ganji ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Reactive Oxygen ◽  
Thiobarbituric Acid ◽  
Protein Carbonyl ◽  
Breast Cancer Cell Lines ◽  
Oxygen Species ◽  
Her2 Positive

Background: The reactive oxygen species (ROS) generated in the biological systems play an important role in pathological conditions and specific normal cellular processes, such as signaling pathways and drug sensitivity. Methods: Intracellular ROS was determined using (2'-7'dichlorofluorescin diacetate) DCFH-DA fluorimetric probe, malondialdehyde as lipid peroxidation index detected by the Thiobarbituric acid reactive substances method. Cells' protein carbonyl contents were assessed with 2,4-Dinitrophenylhydrazine (DNPH) derivatization spectrophotometrically at 360-385 nm. Results: The oxidative stress induces ROS (p?0.05), MDA (Malondialdehyde) (p?0.05), and protein carbonylation (p?0.01) was significantly higher in HER2-positive BT-474, SK-BR-3, and MDA-MB-453 compared to the HER2-negative MDA-MB-231 and MCF-7 cell lines. Conclusion: We hypothesized that increased oxidative stress in HER2-positive cell lines is due to the oncogenic function of the HER2 and PI3K/Akt signaling activation, resulting in glycolysis induction. It is assumed that HER2-positive cell lines with high ROS levels are more vulnerable to further damage by increased ROS levels induced by pro-oxidant anticancer agents.

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