Diclofenac Potentiates Sorafenib-Based Treatments of Hepatocellular Carcinoma by Enhancing Oxidative Stress

Sorafenib is the first developed systemic treatment for advanced forms of hepatocellular carcinoma, which constitutes the most frequent form of primary liver cancers and is a major global health burden. Although statistically significant, the positive effect of sorafenib on median survival remains modest, highlighting the need to develop novel therapeutic approaches. In this report, we introduce diclofenac, a nonsteroidal anti-inflammatory drug, as a potent catalyzer of sorafenib anticancer efficacy. Treatment of three different hepatocellular cancer cells (Huh-7, HepG2, and PLC-PRF-5) with sorafenib (5 µM, 24 h) and diclofenac (100 µM, 24 h) significantly increased cancer cell death compared to sorafenib or diclofenac alone. Anti-oxidant compounds, including N-acetyl-cysteine and ascorbic acid, reversed the deleterious effects of diclofenac/sorafenib co-therapy, suggesting that the generation of toxic levels of oxidative stress was responsible for cell death. Accordingly, whereas diclofenac increased production of mitochondrial oxygen reactive species, sorafenib decreased concentrations of glutathione. We further show that tumor burden was significantly diminished in mice bearing tumor xenografts following sorafenib/diclofenac co-therapy when compared to sorafenib or diclofenac alone. Taken together, these results highlight the anticancer benefits of sorafenib/diclofenac co-therapy in hepatocellular carcinoma. They further indicate that combining sorafenib with compounds that increase oxidative stress represents a valuable treatment strategy in hepatocellular carcinoma.

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Atmospheric pressure gas plasma-induced colorectal cancer cell death is mediated by Nox2–ASK1 apoptosis pathways and oxidative stress is mitigated by Srx–Nrf2 anti-oxidant system

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ◽

10.1016/j.bbamcr.2014.08.011 ◽

2014 ◽

Vol 1843 (12) ◽

pp. 2827-2837 ◽

Cited By ~ 64

Author(s):

Musarat Ishaq ◽

Margaret D.M. Evans ◽

Kostya (Ken) Ostrikov

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Cell Death ◽

Cancer Cell ◽

Atmospheric Pressure ◽

Cancer Cell Death ◽

Gas Plasma ◽

Apoptosis Pathways ◽

Anti Oxidant ◽

And Oxidative Stress

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Zinc chelator TPEN induces pancreatic cancer cell death through causing oxidative stress and inhibiting cell autophagy

Journal of Cellular Physiology ◽

10.1002/jcp.28670 ◽

2019 ◽

Vol 234 (11) ◽

pp. 20648-20661 ◽

Cited By ~ 13

Author(s):

Zhen Yu ◽

Ze Yu ◽

ZhenBao Chen ◽

Lin Yang ◽

MingJun Ma ◽

...

Keyword(s):

Oxidative Stress ◽

Pancreatic Cancer ◽

Cell Death ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Cancer Cell Death ◽

Zinc Chelator

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Caspase-2 and oxidative stress underlie the immunogenic potential of high hydrostatic pressure-induced cancer cell death

OncoImmunology ◽

10.1080/2162402x.2016.1258505 ◽

2016 ◽

Vol 6 (1) ◽

pp. e1258505 ◽

Cited By ~ 18

Author(s):

Irena Moserova ◽

Iva Truxova ◽

Abhishek D. Garg ◽

Jakub Tomala ◽

Patrizia Agostinis ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Hydrostatic Pressure ◽

Cancer Cell ◽

High Hydrostatic Pressure ◽

Cancer Cell Death ◽

Caspase 2 ◽

And Oxidative Stress

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2-Methoxyestradiol and Its Combination with a Natural Compound, Ferulic Acid, Induces Melanoma Cell Death via Downregulation of Hsp60 and Hsp90

Journal of Oncology ◽

10.1155/2019/9293416 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Anna Kamm ◽

Paulina Przychodzeń ◽

Alicja Kuban–Jankowska ◽

Antonella Marino Gammazza ◽

Francesco Cappello ◽

...

Keyword(s):

Cell Death ◽

Ferulic Acid ◽

Melanoma Cell ◽

Cell Model ◽

Clinical Importance ◽

Hsp70 Expression ◽

Cellular Model ◽

Anticancer Efficacy ◽

Cancer Cell Death ◽

A375 Melanoma

Melanoma is an aggressive type of skin cancer with one of the highest mortality rates. Notably, its incidence in the last few decades has increased faster than any other cancer. Therefore, searching for novel anticancer therapies is of great clinical importance. In the present study, we investigated the anticancer potential of 2-methoxyestradiol, potent chemotherapeutic, in the A375 melanoma cellular model. In order to furthermore evaluate the anticancer efficacy of 2-methoxyestradiol, we have additionally combined the treatment with a naturally occurring polyphenol, ferulic acid. The results were obtained using the melanoma A375 cellular model. In the study, we used MTT assay, flow cytometry, and western blot techniques. Herein, we have evidenced that the molecular mechanism of action of 2-methoxyestradiol and ferulic acid is partly related to the reduction of Hsp60 and Hsp90 levels and the induction of nitric oxide in the A375 melanoma cell model, while no changes were observed in Hsp70 expression after 2-methoxyestradiol and ferulic acid treatment separately or in combination. This is especially important in case of chemoresistance mechanisms because the accumulation of Hsp70 reduces induction of cancer cell death, thus decreasing antitumour efficacy.

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Effects of Carbazole Derivatives on Neurite Outgrowth and Hydrogen Peroxide-Induced Cytotoxicity in Neuro2a Cells

Molecules ◽

10.3390/molecules24071366 ◽

2019 ◽

Vol 24 (7) ◽

pp. 1366 ◽

Cited By ~ 3

Author(s):

Yoshiko Furukawa ◽

Atsushi Sawamoto ◽

Mizuki Yamaoka ◽

Makiko Nakaya ◽

Yuhzo Hieda ◽

...

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Cell Death ◽

Neurite Outgrowth ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Anti Oxidant ◽

Neuro2a Cells ◽

Cerebral Ischemic

Many studies have demonstrated that oxidative stress plays an important role in several ailments including neurodegenerative diseases and cerebral ischemic injury. Previously we synthesized some carbazole compounds that have anti-oxidant ability in vitro. In this present study, we found that one of these 22 carbazole compounds, compound 13 (3-ethoxy-1-hydroxy-8- methoxy-2-methylcarbazole-5-carbaldehyde), had the ability to protect neuro2a cells from hydrogen peroxide-induced cell death. It is well known that neurite loss is one of the cardinal features of neuronal injury. Our present study revealed that compound 13 had the ability to induce neurite outgrowth through the PI3K/Akt signaling pathway in neuro2a cells. These findings suggest that compound 13 might exert a neurotrophic effect and thus be a useful therapy for the treatment of brain injury.

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Oxidative Stress-Driven Autophagy acROSs Onset and Therapeutic Outcome in Hepatocellular Carcinoma

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6050123 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Fabio Ciccarone ◽

Serena Castelli ◽

Maria Rosa Ciriolo

Keyword(s):

Oxidative Stress ◽

Hepatocellular Carcinoma ◽

Cell Death ◽

Viral Infections ◽

Apoptotic Cell ◽

Oxygen Species ◽

Suppressor Mechanism ◽

Ros Burst ◽

Therapeutic Compounds ◽

Chemotherapeutic Interventions

Reactive oxygen species- (ROS-) mediated autophagy physiologically contributes to management of cell homeostasis in response to mild oxidative stress. Cancer cells typically engage autophagy downstream of ROS signaling derived from hypoxia and starvation, which are harsh environmental conditions that need to be faced for cancer development and progression. Hepatocellular carcinoma (HCC) is a solid tumor for which several environmental risk factors, particularly viral infections and alcohol abuse, have been shown to promote carcinogenesis via augmentation of oxidative stress. In addition, ROS burst in HCC cells frequently takes place after administration of therapeutic compounds that promote apoptotic cell death or even autophagic cell death. The interplay between ROS and autophagy (i) in the disposal of dysfunctional mitochondria via mitophagy, as a tumor suppressor mechanism, or (ii) in the cell survival adaptive response elicited by chemotherapeutic interventions, as a tumor-promoting event, will be depicted in this review in relation to HCC development and progression.

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Sorafenib-Mediated Targeting of the AAA+ ATPase p97/VCP Leads to Disruption of the Secretory Pathway, Endoplasmic Reticulum Stress, and Hepatocellular Cancer Cell Death

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-12-0516 ◽

2012 ◽

Vol 11 (12) ◽

pp. 2610-2620 ◽

Cited By ~ 48

Author(s):

Ping Yi ◽

Arisa Higa ◽

Said Taouji ◽

Mariana G. Bexiga ◽

Esther Marza ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Endoplasmic Reticulum Stress ◽

Cancer Cell ◽

Secretory Pathway ◽

Hepatocellular Cancer ◽

Aaa Atpase ◽

Cancer Cell Death

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The Activation of Endothelial Cells Relies on a Ferroptosis-Like Mechanism: Novel Perspectives in Management of Angiogenesis and Cancer Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.656229 ◽

2021 ◽

Vol 11 ◽

Author(s):

Filipa Lopes-Coelho ◽

Filipa Martins ◽

Ana Hipólito ◽

Cindy Mendes ◽

Catarina O. Sequeira ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Cell Death ◽

Cancer Cell ◽

Lipid Peroxides ◽

Fourth Generation ◽

Road Map ◽

Cancer Cell Death ◽

Lethal Level ◽

On The Road

The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.

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Role of CNC1 gene in TDP-43 aggregation-induced oxidative stress-mediated cell death in S. cerevisiae model of ALS

10.1101/2020.03.05.978411 ◽

2020 ◽

Author(s):

Vidhya Bharathi ◽

Amandeep Girdhar ◽

Basant K Patel

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Stress Response ◽

Molecular Mechanisms ◽

Motor Neuron Diseases ◽

C Protein ◽

Cell Death Pathway ◽

Cyclin C ◽

Dependent Cell ◽

Anti Oxidant

ABSTRACTTDP-43 is a multi-functional ribonucleoprotein that is also found deposited as hyper-phosphorylated and ubiquitinated TDP-43 inclusions in the brain and spinal cord of the patients of the motor neuron diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Till date, how the cell death ensues is not fully deciphered although several molecular mechanisms of the TDP-43 toxicity such as impairments of endocytosis and chromatin remodelling, mis-regulations of autophagy and proteasome function, mis-localization to the mitochondria and generation of oxidative stress etc., have been proposed. A predominantly nuclear protein, Cyclin C, can regulate the oxidative stress response by affecting the transcription of stress response genes and also by translocation to the cytoplasm for the activation of the mitochondrial fragmentation-dependent cell death pathway. Using the well-established yeast model of TDP-43 aggregation and toxicity, we examined here whether upon TDP-43 aggregation, the cell survival depends on the presence of the CNC1 gene that encodes Cyclin C protein or other genes that encode proteins that function in conjunction with Cyclin C, such as the DNM1, FIS1 and MED13 genes. We found that the TDP-43 toxicity is significantly reduced in the yeast deleted for the CNC1 or DNM1 genes. Importantly, the rescue of TDP-43 toxicity in these yeast deletion backgrounds required the presence of functional mitochondria. Also, the deletion of YBH3 gene, which encodes for a protein involved in the mitochondria-dependent apoptosis, also reduced the TDP-43 toxicity. Furthermore, Cyclin C-YFP was observed to localize from the nucleus to the cytoplasm in response to the TDP-43 co-expression. Also, this cytoplasmic localization of Cyclin C was prevented by the addition of an anti-oxidant molecule, N-acetyl-cysteine. Taken together, our data suggest that Cyclin C, Dnm1 and Ybh3 proteins are important in mediating the TDP-43-induced oxidative stress-mediated cell death in the S. cerevisiae model.

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