scholarly journals Concurrent Reactive Oxygen Species Generation and Aneuploidy Induction Contribute to Thymoquinone Anticancer Activity

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5136
Author(s):  
Mohammed Al-Hayali ◽  
Aimie Garces ◽  
Michael Stocks ◽  
Hilary Collins ◽  
Tracey D. Bradshaw
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Reactive Oxygen ◽  
Biologically Active ◽  
Ros Generation ◽  
Oxygen Species ◽  
Hct 116 ◽  
Hct 116 Cells ◽  
Transformed Cell Lines

Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa. Many studies have confirmed its anticancer actions. Herein, we investigated the different anticancer activities of, and considered resistance mechanisms to, TQ. MTT and clonogenic data showed TQ’s ability to suppress breast MDA-MB-468 and T-47D proliferation at lower concentrations compared to other cancer and non-transformed cell lines tested (GI50 values ≤ 1.5 µM). Flow-cytometric analyses revealed that TQ consistently induced MDA-MB-468 and T-47D cell-cycle perturbation, specifically inducing pre-G1 populations. In comparison, less sensitive breast MCF-7 and colon HCT-116 cells exhibited only transient increases in pre-G1 events. Annexin V/PI staining confirmed apoptosis induction in MDA-MB-468 and HCT-116 cells, which was continuous in the former and transient in the latter. Experiments revealed the role of reactive oxygen species (ROS) generation and aneuploidy induction in MDA-MB-468 cells within the first 24 h of treatment. The ROS-scavenger NAD(P)H dehydrogenase (quinone 1) (NQO1; DT-diaphorase) and glutathione (GSH) were implicated in resistance to TQ. Indeed, western blot analyses showed that NQO1 is expressed in all cell lines in this study, except those most sensitive to TQ-MDA-MB-468 and T-47D. Moreover, TQ treatment increased NQO1 expression in HCT-116 in a concentration-dependent fashion. Measurement of GSH activity in MDA-MB-468 and HCT-116 cells found that GSH is similarly active in both cell lines. Furthermore, GSH depletion rendered these cells more sensitive to TQ’s antiproliferative actions. Therefore, to bypass putative inactivation of the TQ semiquinone metabolite, the benzylamine analogue was designed and synthesised following modification of TQ’s carbon-3 atom. However, the structural modification negatively impacted potency against MDA-MB-468 cells. In conclusion, we disclose the following: (i) The anticancer activity of TQ may be a consequence of ROS generation and aneuploidy; (ii) Early GSH depletion could substantially enhance TQ’s anticancer activity; (iii) Benzylamine substitution at TQ’s carbon-3 failed to enhance anticancer activity.

GNG11 (G-protein subunit γ 11) suppresses cell growth with induction of reactive oxygen species and abnormal nuclear morphology in human SUSM-1 cells

2017 ◽  
Vol 95 (4) ◽  
pp. 517-523 ◽  
Author(s):  
Yuki Takauji ◽  
Ikuru Kudo ◽  
Atsuki En ◽  
Ryo Matsuo ◽  
Mohammad Nazir Hossain ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
G Protein ◽  
Cell Lines ◽  
Hela Cells ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Nuclear Morphology ◽  
Oxygen Species ◽  
Protein Subunit ◽  
Regulatory Relationship

Enforced expression of GNG11, G-protein subunit γ 11, induces cellular senescence in normal human diploid fibroblasts. We here examined the effect of the expression of GNG11 on the growth of immortalized human cell lines, and found that it suppressed the growth of SUSM-1 cells, but not of HeLa cells. We then compared these two cell lines to understand the molecular basis for the action of GNG11. We found that expression of GNG11 induced the generation of reactive oxygen species (ROS) and abnormal nuclear morphology in SUSM-1 cells but not in HeLa cells. Increased ROS generation by GNG11 would likely be caused by the down-regulation of the antioxidant enzymes in SUSM-1 cells. We also found that SUSM-1 cells, even under normal culture conditions, showed higher levels of ROS and higher incidence of abnormal nuclear morphology than HeLa cells, and that abnormal nuclear morphology was relevant to the increased ROS generation in SUSM-1 cells. Thus, SUSM-1 and HeLa cells showed differences in the regulation of ROS and nuclear morphology, which might account for their different responses to the expression of GNG11. Thus, SUSM-1 cells may provide a unique system to study the regulatory relationship between ROS generation, nuclear morphology, and G-protein signaling.

scholarly journals Mutation at position 5628 in the mitochondrial tRNAAla gene in a Chinese pedigree with maternally diabetes mellitus

2019 ◽  
Author(s):  
Ke Li ◽  
Lijun Wu ◽  
Wei Lin ◽  
Tianlan Zhao ◽  
Qiang Qi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Reactive Oxygen Species ◽  
Protein Synthesis ◽  
Cell Lines ◽  
Reactive Oxygen ◽  
Molecular Characteristics ◽  
Ros Generation ◽  
Oxygen Species ◽  
Cellular Models ◽  
Mitochondrial Diabetes

Abstract Background: To investigate the clinical, genetic and molecular characteristics of mitochondrial diabetes mellitus (MDM). Methods: Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. The mitochondrial function including mitochondrial tRNAAla levels, protein synthesis, membrane potential, adenosine triphosphate (ATP) production, and reactive oxygen species (ROS) generation were measured using lymphoblastoid cell lines carrying the m.5628T>C mutation and 2 controls .Results: We observed differences in the severity and age of onset in diabetes in affected maternally-related individuals, and through amolecular of the complete mitochondrial genome in this family, we identified a homoplasmic m.5628T>C mutation, located at conventional position 31 of tRNAAla, and we further detected distinct sets of mtDNA polymorphisms belonging to haplogroup L1. The identified mutation was further found be important for tRNA identity and stability. Using cellular models, we were able to determine that the respiratory deficiency caused arising as a consequence of the m.5628T>C mutation led to decreased efficiency of mitochondrial tRNAAla levels, protein synthesis, mitochondrial ATP synthesis and a reduced mitochondrial membrane potential.These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cell lines. Conclusions: These data provide a direct evidence that novel m.5628T>C mutation may be associated with MDM, thus, offering novel insights into the understanding of pathophysiology of MDM.

scholarly journals The Cytotoxic and Apoptotic Effects of the Brown Algae Colpomenia sinuosa are Mediated by the Generation of Reactive Oxygen Species

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1993
Author(s):  
Reem Al Monla ◽  
Zeina Dassouki ◽  
Achraf Kouzayha ◽  
Yahya Salma ◽  
Hala Gali-Muhtasib ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Brown Algae ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cancer Proliferation ◽  
Morphological Alterations ◽  
Migration Potential ◽  
Hct 116 ◽  
Tumorigenic Cells ◽  
Hct 116 Cells

Brown algae are a novel resource of biogenic molecules, however few studies have been conducted in the Mediterranean to assess the cytotoxic mechanisms of algal-derived compounds. This study focuses on the antineoplastic activity of extracts from non-investigated algae of the Lebanese coast, Colpomenia sinuosa. Extracts’ antineoplastic activities were evaluated by MTT and trypan blue on different tumorigenic cells. Results indicated that the most potent extract was obtained by soxhlet using dichloromethane:methanol solvent (DM soxhlet) against HCT-116. Wound healing assay confirmed that this extract decreased the migration potential of HCT-116 cells with minimal effects on non-tumorigenic cells. It also induced an increase in the subG1 population as determined by flow cytometry. Western blot analysis demonstrated that apoptosis in treated HCT-116 cells was induced via upregulation of p21 protein and downregulation of the anti-apoptotic Bcl 2, which led to caspases activation. The latter, catalyzes the degradation of PARP-1, and thus suppresses cancer proliferation. Morphological alterations, further confirmed apoptosis. A strong pro-oxidant activity evidenced by the enhanced generation of reactive oxygen species (ROS) was observed in HCT-116 treated cells. Interestingly, a strong antioxidant effectively blocked effect induced by the extract. These results indicate that C. sinuosa is a source of bioactive compounds possessing pro-apoptotic and anti-migratory efficacy.

A mitochondria targeting artesunate prodrug-loaded nanoparticle exerting anticancer activity via iron-mediated generation of the reactive oxygen species

2019 ◽  
Vol 55 (33) ◽  
pp. 4781-4784 ◽  
Author(s):  
Zhigang Chen ◽  
Xiaoxu Kang ◽  
Yixin Wu ◽  
Haihua Xiao ◽  
Xuzi Cai ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Activity ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Aliphatic Chain ◽  
Oxygen Species ◽  
Mitochondria Targeting ◽  
Anticancer Prodrug

An artesunate anticancer prodrug with a long aliphatic chain N,N′-bis(dodecyl)-l-glutamic diamide was developed for nanoparticle via iron-mediated ROS generation.

scholarly journals 2-Sulfonylpyrimidines: Mild alkylating agents with anticancer activity toward p53-compromised cells

2016 ◽  
Vol 113 (36) ◽  
pp. E5271-E5280 ◽  
Author(s):  
Matthias R. Bauer ◽  
Andreas C. Joerger ◽  
Alan R. Fersht
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Target Genes ◽  
Alkylating Agents ◽  
Reactive Oxygen ◽  
Glutathione Depletion ◽  
Target Cells ◽  
Oxygen Species

The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53’s oncogenic mutants are just destabilized and rapidly aggregate, and are targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity in several cell lines, especially those with mutationally compromised p53. PK11007 acted by two routes: p53 dependent and p53 independent. PK11007 stabilized p53 in vitro via selective alkylation of two surface-exposed cysteines without compromising its DNA binding activity. Unstable p53 was reactivated by PK11007 in some cancer cell lines, leading to up-regulation of p53 target genes such as p21 and PUMA. More generally, there was cell death that was independent of p53 but dependent on glutathione depletion and associated with highly elevated levels of reactive oxygen species and induction of endoplasmic reticulum (ER) stress, as also found for the anticancer agent PRIMA-1MET(APR-246). PK11007 may be a lead for anticancer drugs that target cells with nonfunctional p53 or impaired reactive oxygen species (ROS) detoxification in a wide variety of mutant p53 cells.

scholarly journals Reactive Oxygen Species in Host Plant Are Required for an Early Defense Response against Attack of Stagonospora nodorum Berk. Necrotrophic Effectors SnTox

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1586
Author(s):  
Svetlana Veselova ◽  
Tatyana Nuzhnaya ◽  
Guzel Burkhanova ◽  
Sergey Rumyantsev ◽  
Igor Maksimov
Keyword(s):  
Reactive Oxygen Species ◽  
Early Stage ◽  
Reactive Oxygen ◽  
Triticum Aestivum L ◽  
Redox Status ◽  
Stagonospora Nodorum ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Necrotrophic Effectors

Reactive oxygen species (ROS) play a central role in plant immune responses. The most important virulence factors of the Stagonospora nodorum Berk. are multiple fungal necrotrophic effectors (NEs) (SnTox) that affect the redox-status and cause necrosis and/or chlorosis in wheat lines possessing dominant susceptibility genes (Snn). However, the effect of NEs on ROS generation at the early stages of infection has not been studied. We studied the early stage of infection of various wheat genotypes with S nodorum isolates -Sn4VD, SnB, and Sn9MN, carrying a different set of NE genes. Our results indicate that all three NEs of SnToxA, SnTox1, SnTox3 significantly contributed to cause disease, and the virulence of the isolates depended on their differential expression in plants (Triticum aestivum L.). The Tsn1–SnToxA, Snn1–SnTox1and Snn3–SnTox3 interactions played an important role in inhibition ROS production at the initial stage of infection. The Snn3–SnTox3 inhibited ROS production in wheat by affecting NADPH-oxidases, peroxidases, superoxide dismutase and catalase. The Tsn1–SnToxA inhibited ROS production in wheat by affecting peroxidases and catalase. The Snn1–SnTox1 inhibited the production of ROS in wheat by mainly affecting a peroxidase. Collectively, these results show that the inverse gene-for gene interactions between effector of pathogen and product of host sensitivity gene suppress the host’s own PAMP-triggered immunity pathway, resulting in NE-triggered susceptibility (NETS). These results are fundamentally changing our understanding of the development of this economical important wheat disease.

scholarly journals CBIO-07. CELL DEATH INDUCED BY AN OSCILLATING MAGNETIC FIELD IN PATIENT DERIVED GLIOBLASTOMA CELLS IS MEDIATED BY REACTIVE OXYGEN SPECIES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
Shashank Hambarde ◽  
Martyn Sharpe ◽  
David Baskin ◽  
Santosh Helekar
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cell Viability ◽  
Cortical Neurons ◽  
Reactive Oxygen ◽  
Great Promise ◽  
Antioxidant Vitamin ◽  
Ros Generation ◽  
Oxygen Species ◽  
Novel Therapy

Abstract Noninvasive cancer therapy with minimal side effects would be ideal for improving patient outcome in the clinic. We have developed a novel therapy using strong rotating magnets mounted on a helmet. They generate oscillating magnetic fields (OMF) that penetrate through the skull and cover the entire brain. We have demonstrated that OMF can effectively kill patient derived glioblastoma (GBM) cells in cell culture without having cytotoxic effects on cortical neurons and normal human astrocytes (NHA). Exposure of GBM cells to OMF reduced the cell viability by 33% in comparison to sham-treated cells (p< 0.001), while not affecting NHA cell viability. Time lapse video-microscopy for 16 h after OMF exposure showed a marked elevation of mitochondrial reactive oxygen species (ROS), and rapid apoptosis of GBM cells due to activation of caspase 3. Addition of a potent antioxidant vitamin E analog Trolox effectively blocked OMF-induced GBM cell death. Furthermore, OMF significantly potentiated the cytotoxic effect of the pro-oxidant Benzylamine. The results of our studies demonstrate that OMF-induced cell death is mediated by ROS generation. These results demonstrate a potent oncolytic effect on GBM cells that is novel and unrelated to any previously described therapy, including a very different mechanism of action and different technology compared to Optune therapy. The effect is very powerful, and unlike Optune, can be seen within hours after initiation of treatment. We believe that this technology holds great promise for new, effective and nontoxic treatment of glioblastoma.

scholarly journals Marine Antimicrobial Peptide TP4 Exerts Anticancer Effects on Human Synovial Sarcoma Cells via Calcium Overload, Reactive Oxygen Species Production and Mitochondrial Hyperpolarization

Marine Drugs ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 93
Author(s):  
Bor-Chyuan Su ◽  
Giun-Yi Hung ◽  
Yun-Chieh Tu ◽  
Wei-Chen Yeh ◽  
Meng-Chieh Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Antimicrobial Peptide ◽  
Anticancer Activity ◽  
Synovial Sarcoma ◽  
Uncoupling Protein ◽  
Reactive Oxygen ◽  
Calcium Overload ◽  
Oxygen Species ◽  
Sarcoma Cells

Synovial sarcoma is a rare but aggressive soft-tissue sarcoma associated with translocation t(X;18). Metastasis occurs in approximately 50% of all patients, and curative outcomes are difficult to achieve in this group. Since the efficacies of current therapeutic approaches for metastatic synovial sarcoma remain limited, new therapeutic agents are urgently needed. Tilapia piscidin 4 (TP4), a marine antimicrobial peptide, is known to exhibit multiple biological functions, including anti-bacterial, wound-healing, immunomodulatory, and anticancer activities. In the present study, we assessed the anticancer activity of TP4 in human synovial sarcoma cells and determined the underlying mechanisms. We first demonstrated that TP4 can induce necrotic cell death in human synovial sarcoma AsKa-SS and SW982 cells lines. In addition, we saw that TP4 initiates reactive oxygen species (ROS) production and downregulates antioxidant proteins, such as uncoupling protein-2, superoxide dismutase (SOD)-1, and SOD-2. Moreover, TP4-induced mitochondrial hyperpolarization is followed by elevation of mitochondrial ROS. Calcium overload is also triggered by TP4, and cell death can be attenuated by a necrosis inhibitor, ROS scavenger or calcium chelator. In our experiments, TP4 displayed strong anticancer activity in human synovial sarcoma cells by disrupting oxidative status, promoting mitochondrial hyperpolarization and causing calcium overload.

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