Reactive Oxygen Species Production In Cancer Cells Research Articles

Comparison of the potential of extracts from the flower, fruit pulp, and seed of Cassia fistula L. on MCF-7 breast cancer cell growth and cell migration

This study aimed to determine the anticancer effects of extracts prepared from various parts of Cassia fistula L. (CF), i.e., flower extract (FE), fruit pulp extract (FPE) and seed extract (SE), on MCF-7 breast cancer cells. The anticancer effects of the extracts were assessed for cell toxicity, cell proliferation, cell migration, cell apoptosis, and production of reactive oxygen species (ROS). Effective cancer treatments have focused on inhibiting epidermal growth factor receptor (EGFR) signalling. Thus, the expression of EGFR protein after extract-treated cells was also determined. Following a 72 incubation, high potential cytotoxicity on MCF-7 cells was observed after SE treatment, followed by FE and FPE treatment. FE, FPE, and SE significantly inhibited cell growth at concentrations of 500, 1,000, and 250 µg/mL, respectively. Also, FE, FPE, and SE markedly suppressed migration of MCF-7 cells at concentrations of 500, 500, and 100 µg/mL, respectively. These results can be concluded that SE had the highest potential anticancer effect on MCF-7 cells when compared with FE and FPE. Thus, SE might be a potential source of preventative and therapeutic agents against breast cancer. Since most anticancer drugs cause ROS production in cancer cells and it is known that ROS induce cell death; therefore, cell apoptosis and ROS formation induced by SE were further studied. The results showed SE induced MCF-7 cell apoptosis in a concentration-dependent way. SE caused a significant increase in ROS formation when compared with the control group. Western blot analysis showed low levels of EGFR protein expression after SE-treated cells at 1,000 mg/mL. Therefore, besides ROS formation, it may be concluded that the downregulation of EGFR protein expression is potentially one of the fundamental mechanisms driving the anticancer effects of SE.

Abstract 1371: Tumor treating fields exposure causes an imbalance of reactive oxygen homeostasis likely through the cytosolic function of the fanconi′s anemia genes

Abstract The use of Tumor Treating Fields (TTFields) has been shown to significantly benefit patients with non-resectable locally advanced or metastatic glioblastoma and malignant pleural mesothelioma. Although the disruption of mitosis that was initially attributed as the mechanism of tumor cell killing, in subsequent studies, it has been shown that TTFields inhibits DNA damage repair by downregulating DNA repair genes and proteins, including those associated with Fanconi's Anemia (FA). As a result, radiation-induced DNA damage repair is reduced and DNA replication fork protection is impaired, leading to replication stress and replication fork collapse. As the FA genes play a critical role in multiple repair pathways, TTFields is likely to increase susceptibility to other chemo agents besides radiation that cause DNA damage which is repaired by FA-dependent DNA repair and replication fork maintenance pathways in nuclei. In addition to their nuclear role, the FA proteins also regulate mitophagy in the cytosol. Using a panel of non-small cell lung cancer cell lines, it was found that TTFields exposure disrupted the clearance of damaged mitochondria despite the presence of a well-defined membrane markers for autophagosomal destruction of damaged mitochondria, that being PINK1 and parkin. Analysis of electron micrographs revealed disrupted mitochondrial cristae, while radical oxygen metabolism studies identified an imbalance leading to the production of reactive oxygen species (ROS) and ultimately, cell death. The downregulation of key mitochondrial genes including DAPIT, OSCP1, ATP5S, ATP5B and COXIV that are related to electron transport and mitochondrial integrity was confirmed by gene expression analysis. The small molecule dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, changes the metabolic state of cancer cells from cytoplasmic glycolysis to mitochondrial glucose oxidation, resulting in a decrease in mitochondrial membrane potential and an increase in ROS production in cancer cells. A combination of DCA with TTFields is therefore being investigated as a means of exploiting mitochondrial dysfunction caused by TTFields. The inhibition of mitophagy suggests a new mechanism of action for TTFields exposure tied to the downregulation of the FA pathway genes, the result being both nuclear and cytosolic perturbations in cell homeostasis. This study offers an evidence-based rationale for combining TTFields with various chemotherapy agents that may cause DNA damage, induce replication stress, and expose cells to radical oxygen byproducts of disrupting electron transport chains and the disruption of mitochondrial integrity. Citation Format: Narasimha Kumar Karanam, Michael Story. Tumor treating fields exposure causes an imbalance of reactive oxygen homeostasis likely through the cytosolic function of the fanconi′s anemia genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1371.

The Self-Administered Use of Complementary and Alternative Medicine (CAM) Supplements and Antioxidants in Cancer Therapy and the Critical Role of Nrf-2-A Systematic Review.

Complementary and alternative medicine (CAM) supplements are widely used by cancer patients. Dietary supplements, vitamins and minerals, herbal remedies, and antioxidants are especially popular. In a systematic literature review, 37 studies, each including more than 1000 participants, on CAM, dietary supplement, and vitamin use among cancer patients were identified. Accordingly, cancer patients use antioxidants such as vitamin C (from 2.6% (United Kingdom) to 41.6% (United States)) and vitamin E (from 2.9% (China) to 48% (United States)). Dietary supplements and vitamins are taken for different reasons, but often during conventional cancer treatment involving chemotherapy or radiotherapy and in a self-decided manner without seeking medical advice from healthcare professionals. Drug-drug interactions with dietary supplements or vitamins involving multiple signaling pathways are well described. Since most of the anticancer drugs generate reactive oxygen species (ROS), an adaptive stress response of healthy and malignant cells, mainly driven by the Nrf-2-Keap I network, can be observed. On the one hand, healthy cells should be protected from ROS-overproducing chemotherapy and radiotherapy; on the other hand, ROS production in cancer cells is a "desirable side effect" during anticancer drug treatment. We here describe the paradoxical use of antioxidants and supplements during cancer therapy, possible interactions with anticancer drugs, and the involvement of the Nrf-2 transcription factor.

Understanding the Mechanism of Action of Melatonin, Which Induces ROS Production in Cancer Cells.

Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. In this context, tumor cells have an altered redox balance compared to normal cells, which can be targeted as an antitumoral therapy by ROS levels and by decreasing the capacity of the antioxidant system, leading to programmed cell death. Melatonin is of particular importance in the development of innovative cancer treatments due to its oncostatic impact and lack of adverse effects. Despite being widely recognized as a pro-oxidant molecule in tumor cells, the mechanism of action of melatonin remains unclear, which has hindered its use in clinical treatments. The current review aims to describe and clarify the proposed mechanism of action of melatonin inducing ROS production in cancer cells in order to propose future anti-neoplastic clinical applications.

Pro-Oxidant Actions of Carotenoids in Triggering Apoptosis of Cancer Cells: A Review of Emerging Evidence.

Carotenoids are well known for their potent antioxidant function in the cellular system. However, in cancer cells with an innately high level of intracellular reactive oxygen species (ROS), carotenoids may act as potent pro-oxidant molecules and trigger ROS-mediated apoptosis. In recent years, the pro-oxidant function of several common dietary carotenoids, including astaxanthin, β-carotene, fucoxanthin, and lycopene, has been investigated for their effective killing effects on various cancer cell lines. Besides, when carotenoids are delivered with ROS-inducing cytotoxic drugs (e.g., anthracyclines), they can minimize the adverse effects of these drugs on normal cells by acting as antioxidants without interfering with their cytotoxic effects on cancer cells as pro-oxidants. These dynamic actions of carotenoids can optimize oxidative stress in normal cells while enhancing oxidative stress in cancer cells. This review discusses possible mechanisms of carotenoid-triggered ROS production in cancer cells, the activation of pro-apoptotic signaling by ROS, and apoptotic cell death. Moreover, synergistic actions of carotenoids with ROS-inducing anti-cancer drugs are discussed, and research gaps are suggested.

N-Acetyl-l-cysteine Enhances the Effect of Selenium Nanoparticles on Cancer Cytotoxicity by Increasing the Production of Selenium-Induced Reactive Oxygen Species

Peritoneal carcinomatosis (PC) has an extremely poor prognosis, which leads to a significantly decreased overall survival in patients with peritoneal implantation of cancer cells. Administration of sodium selenite by intraperitoneal injection is highly effective in inhibiting PC. Our previous study found that selenium nanoparticles (SeNPs) have higher redox activity and safety than sodium selenite. In the present study, we examined the therapeutic effect of SeNPs on PC and elucidated the potential mechanism. Our results revealed that intraperitoneal delivery of SeNPs to cancer cells in the peritoneal cavity of mice at a tolerable dose was beneficial for prolonging the survival time of mice, even better than the optimal dose of cisplatin. The underlying mechanism involved in SeNP-induced reactive oxygen species (ROS) production caused protein degradation and apoptotic response in cancer cells. Interestingly, N-acetyl-l-cysteine (NAC), recognized as a ROS scavenger, without reducing the efficacy of SeNPs, enhanced ROS production and cytotoxicity. The effect of NAC was associated with the following mechanisms: (1) the thiol groups in NAC can increase the biosynthesis of endogenous glutathione (GSH), thus increasing the production of SeNP-induced ROS and cytotoxicity and (2) redox cycling of SeNPs was directly driven by thiol groups in NAC to produce ROS. Moreover, NAC, without increasing the systematic toxicity of SeNPs, decreased SeNP-induced lethality in healthy mice. Overall, we demonstrated that SeNPs exert a potential cytotoxicity effect by inducing ROS production in cancer cells; NAC effectively heightens the property of SeNPs in vitro and in vivo.

Novel PKC-ζ to p47 phox interaction is necessary for transformation from blebbishields.

Cancer stem cells are capable of transformation after apoptosis through the blebbishield emergency program. Reactive oxygen species (ROS) play an essential role in transformation. Understanding how ROS are linked to blebbishield-mediated transformation is necessary to develop efficient therapeutics that target the resurrection of cancer stem cells. Here we demonstrate that a novel PKC-ζ to p47phox interaction is required for ROS production in cancer cells. The combined use of the S6K inhibitor BI-D1870 with TNF-α inhibited the PKC-ζ to p47phox interaction, inhibited ROS production, degraded PKC-ζ, and activated caspases-3 and -8 to block transformation from blebbishields. BI-D1870 also inhibited transformation from cycloheximide-generated blebbishields. Thus ROS and the PKC-ζ to p47phox interaction are valid therapeutic targets to block transformation from blebbishields.

Paraptosis and NF-κB activation are associated with protopanaxadiol-induced cancer chemoprevention

BackgroundProtopanaxadiol (PPD) is a triterpenoid that can be prepared from steamed ginseng. PPD possesses anticancer potential via caspase-dependent apoptosis. Whether paraptosis, a type of the caspase-independent cell death, is also induced by PPD has not been evaluated.MethodsCell death, the cell cycle and intracellular reactive oxygen species (ROS) were analyzed by flow cytometry after staining with annexin V/PI, PI/RNase or H2DCFDA. We observed morphological changes by crystal violet staining assay. Mitochondrial swelling was measured by ultraviolet–visible spectrophotometry. The activation of NF-κB was measured by luciferase reporter assay.ResultsAt comparable concentrations of 5-fluorouracil, PPD induced more cell death in human colorectal cancer cell lines HCT-116 and SW-480. We demonstrated that PPD induced paraptosis in these cancer cells. PPD treatment significantly increased the percentage of cancer cells with cytoplasmic vacuoles. After the cells were treated with PPD and cycloheximides, cytoplasmic vacuole generation was inhibited. The paraptotic induction effect of PPD was also supported by the results of the mitochondrial swelling assay. PPD induced ROS production in cancer cells, which activated the NF-κB pathway. Blockage of ROS by NAC or PS-1145 inhibited the activation of NF-κB signaling.ConclusionsPPD induces colorectal cancer cell death in part by induction of paraptosis. The anticancer activity of PPD may be enhanced by antioxidants such as green tea, which also inhibit the activation of NF-κB signaling.