Oxidative Stress In Cancer Cells Research Articles

The Vitamin C Enantiomers Possess a Comparable Potency in the Induction of Oxidative Stress in Cancer Cells but Differ in Their Toxicity.

The use of vitamin C (VC) in high doses demonstrates a potent tumor suppressive effect by mediating a glucose-dependent oxidative stress in Kirsten rat sarcoma (KRAS) mutant cancer cells. VC with arsenic trioxide (ATO) is a promising drug combination that might lead to the development of effective cancer therapeutics. Considering that a tumor suppressive effect of VC requires its high-dose administration, it is of interest to examine the toxicity of two enantiomers of VC (enantiomer d-optical isomer D-VC and natural l-optical isomer L-VC) in vitro and in vivo. We show that the combinations of L-VC with ATO and D-VC with ATO induced a similar cytotoxic oxidative stress in KrasG12D-expressing mutant cancer cells as indicated by a substantial increase in reactive oxidative species (ROS) production and depolarization of mitochondria. To examine the L-VC and D-VC toxicity effects, we administered high doses of D-VC and L-VC to CD1 mice and carried out an evaluation of their toxic effects. The daily injections of L-VC at a dose of 9.2 g/kg for 18 days were lethal to mice, while 80% of mice remained alive following the similar high-dose administration of D-VC. Following the drug injection courses and histopathological studies, we determined that a natural form of VC (L-VC) is more harmful and toxic to mice when compared to the effects caused by the similar doses of D-VC. Thus, our study indicates that the two enantiomers of VC have a similar potency in the induction of oxidative stress in cancer cells, but D-VC has a distinctive lower toxicity in mice compared to L-VC. While the mechanism of a distinctive toxicity between D-VC and L-VC is yet to be defined, our finding marks D-VC as a more preferable option compared to its natural enantiomer L-VC in clinical settings.

Closed‐loop of Catalyzed Lactate Oxidization Synergistically Sensitizes Apoptosis and Ferroptosis for Cancer Therapy

AbstractLactate accumulated in Tumor is a key oncometabolite and associated with various oncogenic processes, including proliferation, invasion, angiogenesis, metastasis, immunosuppression and therapeutic resistance. Particularly, lactate contributes to the apoptosis and ferroptosis resistance in cancer cells. Consequently, blockade of lactate provides a promising opportunity for cancer therapy. However, due to abnormal tumor microenvironment (TME) and intracellular glutathione (GSH) mediated ferroptosis resistance, the current approaches for regulating lactate to sensitize cells to apoptosis and ferroptosis are still challenging. Herein, we developed a catalytic lactate oxidizing liposomes (Lip‐LM) incorporated with lactate oxidase (LOX)‐loaded MnO2 nanoparticles. O2 regenerated from H2O2 constitute closed‐loop of lactate oxidation catalyzed by LOX, enhancing the lactate‐consuming efficacy in TME. Besides, glutathione is consumed by MnO2 to amplify the ferroptosis susceptibility of cancer cells. The results showed that Lip‐LM achieved synergistical apoptosis and ferroptosis to enhance the anti‐tumor efficacy of amplified oxidative stress in cancer cells through the strategy of self‐sufficient O2 supplying and GSH consumption. The results of transcriptomics and proteomics analyses also support the synergistical anti‐tumor mechanisms of Lip‐LM. Hence, it is a promising catalytic nanoplatform combined lactate regulation and oxidative stress amplification and have great potential to further enhance therapeutic outcomes based on synergistical apoptosis and ferroptosis.

Nano iron doped calcium phosphates act as pH-Sensitive and biodegradable peroxidase-like nanozymes for cancer chemodynamic therapy and MRI contrast

All types of cancer are a threat to human health and among the current therapies, the highly invasive chemotherapy is still the standard in several cases. Currently, more specific and less invasive therapies are being developed and chemodynamic therapy arose as a viable alternative. This strategy takes advantage of the tumour biochemical characteristics such as the acidic pH (∼6.0) and the high concentration of H2O2 (∼50 μM–∼1 mM). In these specific conditions, nanoparticles with peroxidase-like catalytic properties can convert H2O2 into highly toxic reactive oxygen species that induce oxidative stress in cancer cells. One of the remarkable advantages of chemodynamic therapy concerns the peroxidase-like activity, which only occurs in specific pH environments, as found in the tumour microenvironment. At the same time, the produced reactive oxygen species are short-lived, meaning that they will not travel outside the tumoral region, thus not affecting healthy surrounding tissues.This work reports on the production and characterization of iron doped calcium phosphate nanoparticles, as a fully biodegradable alternative to existing chemodynamic agents. By incorporating iron in different oxidation states into the lattice through calcium substitution, these nanoparticles exhibit high catalytic conversion of H2O2 into reactive oxygen species, more specifically into the hydroxyl radical, independently of the iron oxidation state. Outstanding results concern the significant toxicity, only obtained at pH 6.0 and in the presence of H2O2, while remaining non-toxic in physiological conditions (pH7.4) when tested against triple negative breast cancer cells, thus proving the specificity of the treatment in tumoral conditions. Moreover, the presented magnetic properties allowed them to produce significant contrast in magnetic resonance imaging, with different results depending on the iron oxidation state.

Oxidative Stress Induced by Chemotherapy: Evaluation of Glutathione and Its Related Antioxidant Enzyme Dynamics in Patients with Colorectal Cancer.

One of the mechanisms of chemotherapy is to increase the oxidative stress of cancer cells, leading to their apoptosis. Glutathione (GSH) and its related antioxidant enzymes might be stimulated to cope with increased oxidative stress during chemotherapy. Here, we studied the fluctuation in oxidative stress and GSH-related antioxidant capacities before tumor resection, after tumor resection, and after resection either with or without chemotherapy in patients with colorectal cancer (CRC). This was a cross-sectional and follow-up design. We followed patients before having tumor resection (pre-resection), one month after tumor resection (post-resection), and after the first scheduled chemotherapy (post-chemo). If patients were required to receive chemotherapy after tumor resection, they were assigned to the chemotherapy group. Eligible patients were scheduled to undergo six to twelve cycles of chemotherapy at 2-week intervals and received single, double, or triple chemotherapeutic drugs as required. Those patients who did not require chemotherapy were assigned to the non-chemotherapy group. Indicators of oxidative stress and GSH-related antioxidant capacities were determined at the above three time points. We found in 48 patients of the chemotherapy group and in 43 patients of the non-chemotherapy group different fluctuations in levels of oxidative stress indicators and GSH-related antioxidant capacities starting from pre-resection, post-resection through the post-chemo period. Both groups showed significantly or slightly increased levels of advanced oxidation protein products (AOPP), GSH, and its related enzymes in tumor tissues compared to adjacent normal tissues. Patients in the chemotherapy group had significantly lower plasma levels of GSH and glutathione disulfide (GSSG), but had significantly higher plasma glutathione peroxidase and glutathione reductase activities than patients in the non-chemotherapy group post-chemo. Plasma levels of malondialdehyde and AOPP were positively or negatively associated with GSH and GSSG levels post-chemo after adjustment for age, sex, and histological grading in patients receiving chemotherapy. These significant associations were, however, not seen in patients without chemotherapy. Patients with CRC may require higher GSH demands to cope with a greater oxidative stress resulting from chemotherapy.

An Effective, Green Synthesis Procedure for Obtaining Coumarin-Hydroxybenzohydrazide Derivatives and Assessment of Their Antioxidant Activity and Redox Status.

In this study, green synthesis of two derivatives of coumarin-hydroxybenzohydrazide, (E)-2,4-dioxo-3-(1-(2-(2,3,4-trihydroxybenzoyl)hydrazyl)ethylidene)-chroman-7-yl acetate (C-HB1), and (E)-2,4-dioxo-3-(1-(2-(3,4,5-trihydroxybenzoyl)hydrazyl)ethylidene)chroman-7-yl acetate (C-HB2) is reported. Using vinegar and ethanol as a catalyst and solvent, the reactions were carried out between 3-acetyl-4-hydroxy-coumarin acetate and corresponding trihydroxybenzoyl hydrazide. The antioxidant potential of these compounds was investigated using the DPPH and ABTS assays, as well as the FRAP test. The obtained results reveal that even at very low concentrations, these compounds show excellent radical scavenging potential. The IC50 values for C-HB1 and C-HB2 in relation to the DPPH radical are 6.4 and 2.5 μM, respectively, while they are 4.5 and 2.0 μM in relation to the ABTS radical. These compounds have antioxidant activity that is comparable to well-known antioxidants such as gallic acid, NDGA, and trolox. These results are in good correlation with theoretical parameters describing these reactions. Moreover, it was found that inhibition of DPPH● follows HAT, while inactivation of ABTS+● follows SET-PT and HAT mechanisms. Additionally, coumarin-hydroxybenzohydrazide derivatives induced moderate cytotoxic activity and show significant potential to modulate redox status in HCT-116 colorectal cancer cells. The cytotoxicity was achieved via their prooxidative activity and ability to induce oxidative stress in cancer cells by increasing O2˙- concentrations, indicated by increased MDA and GSH levels. Thus, ROS manipulation can be a potential target for cancer therapies by coumarins, as cancer cells possess an altered redox balance in comparison to normal cells. According to the ADMET analysis, the compounds investigated show good pharmacokinetic and toxicological profiles similar to vitamin C and gallic acid, which makes them good candidates for application in various fields of industry and medicine.

DMSA-coated IONPs trigger oxidative stress, mitochondrial metabolic reprograming and changes in mitochondrial disposition, hindering cell cycle progression of cancer cells

There is increasing interest in modulating the redox homeostasis of tumors since high levels of reactive oxygen species (ROS) make them more vulnerable to changes in these species. Nanomedicine offers promise in this context as such applications may provoke biological responses that induce ROS production. Indeed, iron oxide nanoparticles (IONPs) can induce ROS accumulation through the so-called Fenton reaction of iron, further augmenting the ROS in tumors and overloading the antioxidant system beyond its capacity, thereby driving oxidative stress to a level that is incompatible with cell survival. Here, three different coatings for IONPs were compared to assess their intrinsic capacity to induce ROS production in cells. Of these coatings, dimercaptosuccinic acid-coated IONPs (DMSA-NPs) provoked the strongest ROS production, which was associated with the ability to reprogram the metabolism of cancer cells. This latter phenomenon involved shutting-down oxidative phosphorylation (OXPHOS), shifting mitochondrial morphology towards a more elongated phenotype, reducing the total mitochondrial mass and ultimately, blocking cell proliferation by inducing G0/G1 cell cycle arrest. Consequently, the data obtained highlights the importance of studying the chemical properties of IONPs, presenting DMSA-NPs as a novel tool to induce oxidative stress in cancer cells and alter their cell fate.

A novel lncRNA FUAT1/TNS4 axis confers chemoresistance by suppressing ROS-mediated apoptosis in gastric cancer.

Reactive oxygen species (ROS) play a vital role in conveying the cytotoxicity and resistance of most chemotherapy drugs. Therefore, gaining a comprehensive understanding of the intricate activities against oxidative stress in cancer cells may provide valuable insights into the discovery of common mechanisms underlying chemoresistance. We identified a novel lncRNA, designated FUAT1, as a key non-genetic player involved in ROS-mediated intrinsic chemoresistance by employing a unique screening strategy based on transcriptome sequencing (RNA-Seq) technology. To further investigate the role of the FUAT1 regulatory axis in chemoresistance, we conducted a series of in vitro and in vivo assays including gain/loss-of-function and rescue experiments. Mechanistically, our findings revealed that FUAT1 upregulates TNS4 by sponging miR-140-5p, which allows gastric cancer cells to survive chemotherapy by inhibiting ROS-mediated apoptosis. Clinically, we observed that the FUAT1/TNS4 regulatory axis is negatively associated with overall survival and progression-free survival among gastric and colon cancer patients treated with 5-FU adjuvant chemotherapy. We devised a novel screening strategy distinct from conventional approaches using drug-resistant strains. Through this approach, we identified the previously unrecognized lncRNA FUAT1/TNS4 axis which plays an important role in ROS-mediated intrinsic chemoresistance. Our findings shed light on fundamental adaptive mechanisms employed by cancer cells to respond to chemotherapy and provide new insights into developing strategies aiming at overcom chemoresistance.

Screening fructosamine-3-kinase (FN3K) inhibitors, a deglycating enzyme of oncogenic Nrf2: Human FN3K homology modelling, docking and molecular dynamics simulations.

Fructosamine-3-kinase (FN3K) is involved in the deglycation of Nrf2, a significant regulator of oxidative stress in cancer cells. However, the intricate functional aspects of FN3K and Nrf2 in breast cancers have not been explored vividly. The objectives of this study are to design the human FN3K protein using homology modeling followed by the screening of several anticancer molecules and examining their efficacy to modulate FN3K activity, Nrf2-mediated antioxidant signalling. Methods pertinent to homology modeling, virtual screening, molecular docking, molecular dynamics simulations, assessment of ADME properties, cytotoxicity assays for anticancer molecules of natural/synthetic origin in breast cancer cells (BT-474, T-47D), and Western blotting were used in this study. The screened anticancer molecules including kinase inhibitors of natural and synthetic origin interacted with the 3-dimensional structure of the catalytic domain in human FN3K protein designed through homology modeling by significant CDOCKER interaction energies. Subsequently, gefitinib, sorafenib, neratinib, tamoxifen citrate, and cyclosporine A enhanced the expression of FN3K in BT-474 cell lines with simultaneous alteration in Nrf2-driven antioxidant signalling. Oxaliplatin significantly downregulated FN3K expression and modulated Nrf2-driven antioxidant signalling when compared to cisplatin and other anticancer drugs. Hence, the study concluded the potential implications of existing anticancer drugs to modulate FN3K activity in breast cancers.

Polyphenolic Carbon Quantum Dots with Intrinsic Reactive Oxygen Species Amplification for Two-Photon Bioimaging and In Vivo Tumor Therapy.

Recent studies indicate that mitochondrial dysfunctions and DNA damage have a critical influence on cell survival, which is considered one of the therapeutic targets for cancer therapy. In this study, we demonstrated a comparative study of the effect of polyphenolic carbon quantum dots (CQDs) on in vitro and in vivo antitumor efficacy. Dual emissive (green and yellow) shape specific polyphenolic CQDs (G-CQDs and Y-CQDs) were synthesized from easily available nontoxic precursors (phloroglucinol), and the antitumor property of the as-synthesized probe was investigated as compared to round-shaped blue emissive CQDs (B-CQDs) derived from well-reported precursor citric acid and urea. The B-CQDs had a nuclei-targeting property, and G-CQDs and Y-CQDs had mitochondria-targeting properties. We have found that the polyphenol containing CQDs (at a dose of 100 μg mL-1) specifically attack mitochondria by excess accumulation, altering the metabolism, inhibiting branching pattern, imbalanced Bax/Bcl-2 homeostasis, and ultimately generating oxidative stress levels, leading to oxidative stress-induced cell death in cancer cells in vitro. We show that G-CQDs are the main cause of oxidative stress in cancer cells because of their ability to produce sufficient •OH- and 1O2 radicals, evidenced by electron paramagnetic resonance spectroscopy and a terephthalic acid test. Moreover, the near-infrared absorption properties of the CQDs were exhibited in two-photon (TP) emission, which was utilized for TP cellular imaging of cancer cells without photobleaching. The in vivo antitumor test further discloses that intratumoral injection of G-CQDs can significantly augment the treatment efficacy of subcutaneous tumors without any adverse effects on BalB/c nude mice. We believe that shape-specific polyphenolic CQD-based nanotheranostic agents have a potential role in tumor therapy, thus proving an insight on treatment of malignant cancers.

Lysosomal cyst(e)ine storage potentiates tolerance to oxidative stress in cancer cells

Cyst(e)ine is a key precursor for the synthesis of glutathione (GSH), which protects cancer cells from oxidative stress. Cyst(e)ine is stored in lysosomes, but its role in redox regulation is unclear. Here, we show that breast cancer cells upregulate major facilitator superfamily domain containing 12 (MFSD12) to increase lysosomal cyst(e)ine storage, which is released by cystinosin (CTNS) to maintain GSH levels and buffer oxidative stress. We find that mTORC1 regulates MFSD12 by directly phosphorylating residue T254, while mTORC1 inhibition enhances lysosome acidification that activates CTNS. This switch modulates lysosomal cyst(e)ine levels in response to oxidative stress, fine-tuning redox homeostasis to enhance cell fitness. MFSD12-T254A mutant inhibits MFSD12 function and suppresses tumor progression. Moreover, MFSD12 overexpression correlates with poor neoadjuvant chemotherapy response and prognosis in breast cancer patients. Our findings reveal the critical role of lysosomal cyst(e)ine storage in adaptive redox homeostasis and suggest that MFSD12 is a potential therapeutic target.

A tumor microenvironment responsive titanium-based nanosonosensitizer for combination sonodynamic-immunotherapy with calcium ion overload

Ultrasound (US)-triggered sonodynamic therapy (SDT) has become a promising method and has attracted considerable attention for cancer therapy due to its high accuracy, deep tissue penetration, and few side effects. However, the therapeutic efficacy of SDT is limited by the hypoxic tumor microenvironment (TME) and the low quantum yield of sonosensitizers. Immunogenic cell death (ICD) induced by calcium ion overload has attracted widespread attention because it can trigger antitumor immune responses and reconstitute tumor immune microenvironment (TIM).In this study, a TME-responsive CaCO3@Pt-TiO2 nanocomposite (CaPT) was engineered, which combined platinum (Pt) nanoparticles and CaCO3 nanoparticles to amplify oxidative stress in cancer cells for cancer sonodynamic immunotherapy. The Pt nanoparticles not only enhanced the reactive oxygen species (ROS) quantum yield of TiO2 during SDT but also catalyzed the decomposition of H2O2 to overcome tumor hypoxia. The CaCO3@Pt-TiO2 nanocomposite responded to the TME and released a large amount of Ca2+, which amplified oxidative stress and triggered robust ICD activation. This process greatly contributed to inflammatory cell infiltration and shifted the TIM from cold to hot. The experimental results confirmed and demonstrated the synergistic therapeutic effects of sonodynamic-immunotherapy in vitro and in vivo. The antitumor mechanisms of sonodynamic immunotherapy were demonstrated by RNA sequencing. This study paves the way for Ti-based nanosensitizers, providing a novel strategy for sonodynamic-cooperated immunotherapy.

Combined effects of two phytoalexins, brassinin and camalexin, on the cells of colorectal origin

Brassinin and camalexin belong to phytoalexins, plant compounds generated in the response to stress. Both compounds are known to be cytotoxic to several cancer cell lines, mainly by inducing oxidative stress and subsequent apoptosis. In the presented study, cytotoxic effects of brassinin and camalexin, individually and, for the first time, after combined exposure, on the cells of normal (CCD-Co18) and cancer (Caco-2) lines originated from colorectal tissues and their proapoptotic impact on Caco-2 cells were studied. The determined IC50 values indicate a clearly higher sensitivity of cancer cells to the tested substances, as well as a stronger cytotoxic effect of camalexin than brassinin. The synergistic effect of both phytoalexins was also demonstrated. Caspase-dependent and independent mechanisms were involved in the final effects. Both tested phytoalexins caused evident, concentration-dependent symptoms of oxidative stress in cancer cells, leading to apoptosis, but in the highest concentrations, also to necrosis. In case of camalexin, signs of pyroptosis were additionally detected.

Artemisinin-More than a Malarial Drug

In Asia, Artemisia annua L. tea and press juice are used to cure malaria and its associated symptoms. Artemisia annua comes under the Anthemideae tribe, which includes the roughly 500 species of Artemisia L., is primarily distributed in Asia, Europe, and North America. Due to the presence of numerous active components or secondary metabolites, artemisia typically exhibits a wide range of bioactivity. The drug’s active component, Artemisinin (ARS), was created as an antimalarial and is used all over the world. It’s interesting to note that the bioactivity is not just used to cure malaria. It is discovered that medications of the ARS type also exhibit anti-cancerous activity in vivo and in vitro. Artemisinin and its analogues have been demonstrated to reduce intracellular free iron levels in cancer cells, which are substantially higher than those in normal cells. Apoptosis, necrosis, necroptosis, tumour-related signal transduction pathways are responses to oxidative stress in cancer cells that are triggered by ARS and its derivatives. Artemisia annua L. extracts contain anti-inflammatory, antioxidant, and antifungal antimicrobial substances. The purpose of this review is to illustrate how artemisinin retrieves various illnesses and conditions. Another objective of ours is to compile an up-to-date report on the various activities of artemisinin

Inhibition of Autophagy and the Cytoprotective Role of Smac Mimetic against ROS-Induced Cancer: A Potential Therapeutic Strategy in Relapse and Chemoresistance Cases in Breast Cancer.

With more than a million deaths each year, breast cancer is the top cause of death in women. Around 70% of breast cancers are hormonally responsive. Although several therapeutic options exist, cancer resistance and recurrence render them inefficient and insufficient. The major key reason behind this is the failure in the regulation of the cell death mechanism. In addition, ROS was also found to play a major role in this problem. The therapeutic benefits of Smac mimetic compound (SMC) BV6 on MCF7 were examined in the current study. Treatment with BV6 reduces viability and induces apoptosis in MCF7 breast cancer cells. BV6 suppresses autophagy and has demonstrated a defensive role in cancer cells against oxidative stress caused by H2O2. Overall, the present investigation shows that SMC has therapeutic and cytoprotective potential against oxidative stress in cancer cells. These Smac mimetic compounds may be used as anti-cancer drugs as well as antioxidants alone or in conjunction with other commonly used antioxidants.

SAR of L-ABBA analogs for GGT1 inhibitory activity and L-ABBA's effect on plasma cysteine and GSH species

Gamma-glutamyl transferase 1 (GGT1) is a critical enzyme involved in the hydrolysis and/or transfer of gamma-glutamyl groups of glutathione, which helps maintain cysteine levels in plasma. In this study, we synthesized L-ABBA analogs to investigate their inhibitory effect on GGT1 hydrolysis and transpeptidase activity, with the goal of defining the pharmacophore of L-ABBA. Our structure–activity relationship (SAR) study revealed that an α-COO- and α-NH3+ group, as well as a two-CH2 unit distance between α-C and boronic acid, are essential for the activity. The addition of an R (alkyl) group at the α-C reduced the activity of GGT1 inhibition, with L-ABBA being the most potent inhibitor among the analogs. Next, we investigated the impact of L-ABBA on plasma levels of cysteine and GSH species, with the expectation of observing reduced cysteine levels and enhanced GSH levels due to its GGT1 inhibition. We administered L-ABBA intraperitoneally and determined the plasma levels of cysteine, cystine, GSH, and GSSG using LCMS. Our results showed time- and dose-dependent L-ABBA changes in total plasma cysteine and GSH levels. This study is the first to demonstrate the regulation of plasma thiol species upon GGT1 inhibition, with plasma cystine levels reduced by up to ∼ 75 % with L-ABBA (0.3 mg/dose). Cancer cells are highly dependent on the uptake of cysteine from plasma for maintaining high levels of intracellular glutathione. Thus, our findings suggest that GGT1 inhibitors, such as L-ABBA, have the potential to be used in GSH reduction thereby inducing oxidative stress in cancer cells and reducing their resistance to many chemotherapeutic agents.

SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells’ sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

Transient Receptor Potential Ankyrin 1 (TRPA1) Channel as a Sensor of Oxidative Stress in Cancer Cells.

Moderate levels of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), fuel tumor metastasis and invasion in a variety of cancer types. Conversely, excessive ROS levels can impair tumor growth and metastasis by triggering cancer cell death. In order to cope with the oxidative stress imposed by the tumor microenvironment, malignant cells exploit a sophisticated network of antioxidant defense mechanisms. Targeting the antioxidant capacity of cancer cells or enhancing their sensitivity to ROS-dependent cell death represent a promising strategy for alternative anticancer treatments. Transient Receptor Potential Ankyrin 1 (TRPA1) is a redox-sensitive non-selective cation channel that mediates extracellular Ca2+ entry upon an increase in intracellular ROS levels. The ensuing increase in intracellular Ca2+ concentration can in turn engage a non-canonical antioxidant defense program or induce mitochondrial Ca2+ dysfunction and apoptotic cell death depending on the cancer type. Herein, we sought to describe the opposing effects of ROS-dependent TRPA1 activation on cancer cell fate and propose the pharmacological manipulation of TRPA1 as an alternative therapeutic strategy to enhance cancer cell sensitivity to oxidative stress.

Biochemical Origin of the Warburg Effect in Light of 15 Years of Research Experience: A Novel Evidence-Based View (An Expert Opinion Article).

Cancer cells strongly upregulate glucose uptake and glycolysis to produce vital biomolecules for cancer cell survival, proliferation, and metastasis as ATP, lipids, proteins, nucleotides, and lactate. The Warburg effect is tumours' unique glucose oxidation to give lactate (not pyruvate) even in the presence of oxygen. Nicotinamide adenine dinucleotide (NAD/NADH.H) is used in glycolysis via glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH). Both catalyse reversible biochemical reactions to produce 1,3-diphosphoglycerate and lactate, respectively. In this expert opinion and based on published evidence, the author suggests that: "In transformed cells and hyperglycolytic cancer cells, the Warburg effect (permanent conversion of pyruvate to lactate) occurs secondary to a vicious cycle and a closed circuit between GAPDH and LDH (reaction of carcinogenesis) causing increased endogenous oxidative stress and subsequent carcinogenesis. Mitochondrial defects in cancer cells cause hyperglycolysis resulting in NADH.H accumulation (produced during GAPDH step) that obligatorily drives LDH to become an irreversible reaction in the direction of lactate formation (Warburg effect) but not pyruvate formation. Likewise, LDH oxidizes NADH.H producing excessive NAD+ that secondarily drives GAPDH reaction to be irreversible to produce NADH.H and so on. Pyruvate is an antioxidant while lactate is pro-oxidant, causing increased endogenous oxidative stress in cancer cells, tumour's hypoxia and obligatory hyperglycolysis with NADH.H overproduction (GAPDH step) to be consumed in the LDH step for lactate production and NAD+ generation (utilized by GAPDH) and so on". This confirms Warburg's origin of cancer cells. Best anticancer applications based on this hypothesis are: breaking this closed vicious circle using siRNA to target GAPDH and LDH, avoiding strong oxidants (as many cancer chemotherapeutics), and using strong antioxidants for causing antioxidant-oxidant antagonism or antioxidant-lactate antagonism to inhibit the Warburg effect. Strong natural antioxidants of prophetic medicine (related to Prophet Muhammad peace be upon him) such as Zamzam water, Nigella sativa, costus, Ajwa date fruit, olive oil, Al-hijamah and natural honey are strongly recommended to prevent and antagonize the Warburg effect.

Dynamic Study of PDT-Induced Oxidative Stress in Cancer Cells Embedded in 3D Collagen Hydrogel Using Genetically Encoded H2O2-Sensor

Photodynamic therapy (PDT) is a rapidly developing cancer treatment method based on the induction of severe oxidative stress in treated cells. Despite widespread clinical application, the molecular mechanisms underlying the photodynamic reaction have not yet been fully elucidated. Currently, the attention of the scientific community has been drawn to the crucial role of the tumor microenvironment which led to transition from using monolayer cultures of cancer cell to complex 3D in vitro models of tumor growth. Such a transition requires modification of existing methods for assessing cellular viability and metabolic responses to therapeutic interventions. We proposed a method for real-time registration of oxidative stress in response to photodynamic therapy in tumor cells embedded in 3D collagen hydrogel. This approach is based on spectroscopic registration of the integral signal from embedded cells expressing genetically encoded fluorescent sensor. The measuring technique does not require the destruction of the hydrogel and allows real-time recording of cell responses to various types of exposure. Using the genetically encoded HyPer sensor, we registered the wave of the secondary production of H 2 O 2 in PDT treated cells lasting for about 1–2 h after the end of irradiation and demonstrated it transient mode, which add new information about mechanisms of PDT-induced oxidative stress. We believe that the proposed approach can become a potent and cost-effective option for real-time registration of cells’ response to various types of exposure and identification of the underlying mechanisms.

Role of green synthesized platinum nanoparticles in cytotoxicity, oxidative stress, and apoptosis of human colon cancer cells (HCT-116)

Progresses in the medicinal application of nanocompounds were accepted for the treatment of cancer. Nanoparticles-based therapy is of benefit for effective biodistribution and specific targeting. The current study investigated the anticancer effect of green synthesized platinum nanoparticles (PtNPs) against colon cancer cells (HCT-116). Flow cytometry and ELISA techniques were employed for detecting apoptotic and oxidative stress markers. Furthermore, PtNPs-lycopene (PtNPs-LP) on cell migration and invasion of HCT-116 cells was also examined. The PtNPs-LP was capable of diminishing cell proliferation and viability of HCT-116 cells in a dose-dependent mode. After treatment with PtNPs-LP, a significant increase in pro-apoptotic Bax and caspase-3 and a decrease in anti-apoptotic Bcl-2 was observed in treated cells that subsequently released cytochrome C into its cytoplasm, initiating cell death. Moreover, PtNPs-LP induced excessive generation of reactive oxygen species (ROS) and oxidative stress in cancer cells. In conclusion, PtNPs-LP exerts an antitumor effect against colon cancer cells via mediating important mechanisms such as cytotoxicity, apoptosis, and oxidative stress.