Oxidative Stress In Cancer Cells Research Articles

Curcumin-encapsulated glucan nanoparticles as an oxidative stress modulator against human hepatic cancer cells

In Hepatitis B patients, the virus targets liver cells, leading to inflammation and liver damage, which can result in severe complications such as liver failure, cirrhosis, and liver cancer. Therapeutic options for liver disease are currently limited. Curcumin, a polyphenol with potential protective effects against chronic diseases like cancer, suffers from poor water solubility, restricting its pharmacological applications. This study explores the encapsulation of curcumin in glucan nanoparticles (NPs) and its impact on oxidative stress in liver cancer cells. Two sizes of curcumin-loaded glucan NPs, GC111 (111 nm) and GC398 (398 nm), were produced with nearly 100 % encapsulation efficiency. Cytotoxicity studies revealed that particle size influences the extent of observed effects, with GC111 NPs causing a greater reduction in cell viability. Additionally, the smaller GC111 NPs demonstrated a higher capacity to induce oxidative stress in cancer cells by stimulating the production of ROS, NO, and the chemokine RANTES in a concentration-dependent manner. These findings suggest that the smaller GC111 NPs are promising candidates for future studies aimed at evaluating oxidative stress-induced tumor cell death mechanisms.

Efficient Encapsulation of β-Lapachone into Self-Immolative Polymer Nanoparticles for Cyclic Amplification of Intracellular Reactive Oxygen Species Stress.

The selective upregulation of intracellular oxidative stress in cancer cells presents a promising approach for effective cancer treatment. In this study, we report the integration of enzyme catalytic amplification and chemical amplification reactions in β-lapachone (Lap)-loaded micellar nanoparticles (NPs), which are self-assembled from reactive oxygen species (ROS)-responsive self-immolative polymers (SIPs). This integration enables cyclic amplification of intracellular oxidative stress in cancer cells. Specifically, we have developed ROS-responsive SIPs with phenylboronic ester triggering motifs and hexafluoroisopropanol moieties in the side chains, significantly enhancing Lap loading efficiency (98%) and loading capacity (33%) through multiple noncovalent interactions. Upon ROS activation in tumor cells, the Lap-loaded micellar NPs disassemble, releasing Lap and generating additional ROS via enzyme catalytic amplification. This process elevates intracellular oxidative stress and triggers polymer depolymerization in a positive feedback loop. Furthermore, the degradation of SIPs via chemical amplification produces azaquinone methide intermediates, which consume intracellular thiol-related substrates, disrupt intracellular redox hemostasis, further intensify oxidative stress, and promote cancer cell apoptosis. This work introduces a strategy to enhance intracellular oxidative stress by combining enzymatic and chemical amplification reactions, providing a potential pathway for the development of highly efficient anticancer agents.

A thermoresponsive metabolic nanomodulator for achieving photochemotherapy-sensitized cancer immunotherapy

The largest obstacle that impedes the successful clinical use of anticancer nanodrugs lies in their unsatisfactory therapeutic performance even if multiple drug treatments are applied, which may cause tumor relapse and drug resistance. Therefore, it is challenging to develop effective nanodrugs that can eradicate tumors with only single injection. Herein, we construct a metabolic nanomodulator (denoted as ISM liposome), where the phototherapeutic dye IR825-NH2, the chemodrug shikonin, and the mitochondrial respiration inhibitor metformin are encapsulated, to closely synergize phototherapy, chemotherapy, and immunotherapy via the laser-triggered on-demand metabolism regulation for realizing robust anticancer potency after only single injection and irradiation. Upon near-infrared laser irradiation, IR825-NH2 can generate reactive oxygen species and mild heat to enable the phototherapeutic cytotoxcity and thermoresponsive release of the loaded drugs. Then, cellular oxygen can be spared by the released metformin via metabolic modulation and be utilized by shikonin to further amplify the oxidative stress in cancer cells. More importantly, the ISM liposome-mediated photochemotherapy can subsequently elicit a strong immunogenic cell death (ICD) effect and sensitize the immunosupressive tumor to the ICD-induced immunotherapy, thereby achieving strong tumor inhibition and even eradication. The metabolic nanomodulator-based photochemotherapy-sensitized cancer immunotherapy may represent a new solution to fight against cancer.

The Protective Effects of Mcl-1 on Mitochondrial Damage and Oxidative Stress in Imiquimod-Induced Cancer Cell Death.

Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development.

Effect of Selol on Tumor Morphology and Biochemical Parameters Associated with Oxidative Stress in a Prostate Tumor-Bearing Mice Model.

Prostate cancer is the leading cause of cancer death in men. Some studies suggest that selenium Se (+4) may help prevent prostate cancer. Certain forms of Se (+4), such as Selol, have shown anticancer activity with demonstrated pro-oxidative effects, which can lead to cellular damage and cell death, making them potential candidates for cancer therapy. Our recent study in healthy mice found that Selol changes the oxidative-antioxidative status in blood and tissue. However, there are no data on the effect of Selol in mice with tumors, considering that the tumor itself influences this balance. This research investigated the impact of Selol on tumor morphology and oxidative-antioxidative status in blood and tumors, which may be crucial for the formulation's effectiveness. Our study was conducted on healthy and tumor-bearing animal models, which were either administered Selol or not. We determined antioxidant enzyme activities (Se-GPx, GPx, GST, and TrxR) spectrophotometrically in blood and the tumor. Furthermore, we measured plasma prostate-specific antigen (PSA) levels, plasma and tumor malondialdehyde (MDA) concentration as a biomarker of oxidative stress, selenium (Se) concentrations and the tumor ORAC value. Additionally, we assessed the impact of Selol on tumor morphology and the expression of p53, BCL2, and Ki-67. The results indicate that treatment with Selol influences the morphology of tumor cells, indicating a potential role in inducing cell death through necrosis. Long-term supplementation with Selol increased antioxidant enzyme activity in healthy animals and triggered oxidative stress in cancer cells, activating their antioxidant defense mechanisms. This research pathway shows promise in understanding the anticancer effects of Selol. Selol appears to increase the breakdown of cancer cells more effectively in small tumors than in larger ones. In advanced tumors, it may accelerate tumor growth if used as monotherapy. Therefore, further studies are necessary to evaluate its efficacy either in combination therapy or for the prevention of recurrence.

Photo-Activated Oxidative Stress Amplifier: A Strategy for Targeting Glutathione Metabolism and Enhancing ROS-Mediated Therapy in Triple-Negative Breast Cancer Treatment.

Amplifying oxidative stress within tumor cells can effectively inhibit the growth and metastasis of triple-negative breast cancer (TNBC). Therefore, the development of innovative nanomedicines that can effectively disrupt the redox balance represents a promising yet challenging therapeutic strategy for TNBC. In this study, an oxidative stress amplifier, denoted as PBCH, comprising PdAg mesoporous nanozyme and a CaP mineralized layer, loaded with GSH inhibitor L-buthionine sulfoximine (BSO), and further surface-modified with hyaluronic acid that can target CD44, is introduced. In the acidic tumor microenvironment, Ca2+ is initially released, thereby leading to mitochondrial dysfunction and eventually triggering apoptosis. Additionally, BSO suppresses the synthesis of intracellular reduced GSH and further amplifies the level of oxidative stress in cancer cells. Furthermore, PdAg nanozyme can be activated by near-infrared light to induce photothermal and photodynamic effects, causing a burst of ROS and simultaneously promoting cell apoptosis via provoking immunogenic cell death. The high-performance therapeutic effects of PBCH, based on the synergistic effect of aforementioned multiple oxidative damage and photothermal ablation, are validated in TNBC cells and animal models, declaring its potential as a safe and effective anti-tumor agent. The proposed approach offers new perspectives for precise and efficient treatment of TNBC.

Dual Stimuli-Responsive Nanoprecursor of Ascorbic Acid and Quinone Methide Disrupting Redox Homeostasis for Cancer Treatment.

Disrupting the redox balance through reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion presents a promising strategy for cancer therapy. Megadoses of ascorbic acid (AA) can induce oxidative stress in cancer cells, leading to cell death. However, achieving enhanced oxidative stress using ultrahigh doses of AA is challenging because of the intricate delivery of high-concentration AA to the targeted sites while the cancer cells could also re-establish more robust redox homeostasis by upregulating antioxidants such as GSH. Recently, quinone methide and its analogues (QMs) have been recognized as effective GSH scavengers, offering a new dimension to accelerate oxidative stress. In this study, we formulated a dual stimuli-responsive nanoprecursor of AA and QM using gold nanoparticles. The nanoprecursor can release AA in response to the intracellular acidic pH in tumor cells, elevating the intracellular ROS levels and triggering the production of ample QMs to quench excessive GSH. This positive feedback mechanism significantly amplifies oxidative stress and disrupts redox homeostasis in cancer cells at a relatively low concentration of AA, leading to selective apoptosis without affecting normal cells. These results highlight the potential of the nanoprecursor as an effective anticancer therapeutic.

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.

Case report: Resolution of pathologic fracture from metastatic non-Hodgkin's lymphoma with compassionate therapy

Broad-spectrum anticancer treatments have limited cell selectivity. The sites of action of these treatments are targeted at blocking cell division and inducing apoptosis. This has a negative impact on the viability and proliferation of healthy cells, which can cause deterioration in the patient's quality of life. In this case report, an older patient with non-Hodgkin's lymphoma, follicular pattern grade 2 with invasion to the L3 vertebra, concluded a combination chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP). However, the patient reported severe and prolonged adverse reactions that caused physical and emotional complaints, thus she refused to continue with the subsequent radiotherapy. Given the impact on quality of life and uncertain survival, by personal decision, the patient started compassionate therapy based on chlorine dioxide (ClO2). This low-cost anticancer agent causes apoptosis in cancer cells by destabilizing the oxidative balance through the release of reactive oxygen species. ClO2 treatment was administered orally and by enema at a concentration below the EPA-reported toxicity threshold, in order to not compromise healthy cells, given that they do not experience the high levels of oxidative stress of cancer cells. During ClO2 treatment, the patient reported no adverse reactions and an increase in bone density was observed in pathological terrain. Rigorous clinical studies are needed to analyze the temporal sequence of the increase in bone density

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.

Pristimerin inhibits thioredoxin reductase in the treatment of non-small cell lung cancer

Elevated cellular oxidative stress is a common marker of cancer cell dysregulation caused by malignant transformation. Thioredoxin reductase (TrxR, encoded by TXNRD) is a crucial enzyme that regulates cellular oxidative stress and the survival of many types of cancer cells. Therefore, targeting TrxR may lead to selective cell death in cancer cells. Pristimerin, a plant triterpenoid, increases the accumulation of reactive oxygen species (ROS) in cells, but its specific regulatory mechanism is unclear. Herein, we found that pristimerin selectively targets TrxR and subsequently induces apoptosis in human non-small cell lung cancer cells, and inhibits tumor growth in vivo with low toxicity to normal cells. Pristimerin was found to inhibit cancer cell growth primarily by inhibiting cellular TrxR, thereby compromising TrxR’s antioxidant function in cells and resulting in the accumulation of oxidized Trx. Furthermore, excessive ROS accumulation stimulated by pristimerin triggered tumor-specific amplification of oxidative stress in cancer cells and ultimately led to targeted destruction of cancer cells. Our data may support the development of potential therapeutic molecules as selective anticancer agents targeting highly enriched TrxR in cancer cells.

Disrupting redox homeostasis for tumor therapy based on PDT/chemo/ferroptosis therapeutic hybrid liposomes.

Synergistic photodynamic therapy (PDT) with other therapeutic modalities can enhance the therapeutic efficacy of tumor treatment and reduce the adverse effects associated with drug leakage and off-target accumulation. However, shaping combined strategies for synergistic therapy remains challenging. Herein, we developed versatile hybrid liposomes self-assembled from Ce6-lipid conjugates and loaded with the chemo drug doxorubicin (DOX) and ferroptosis inducer Fe3O4 nanoparticles for synergistic PDT/chemo/ferroptosis therapy. Abundant ROS are generated by PDT upon 650 nm light irradiation, Fe3O4-mediated Fenton reaction, and DOX-induced apoptosis. Furthermore, amplifying oxidative stress in cancer cells to disrupt cellular redox homeostasis could accelerate tumor cell death through oxidative damage to lipids, proteins, and DNA. Overall, this work highlights liposome-based therapeutic nanoformulations, thus offering a breakthrough redox homeostasis-based synergistic PDT/chemo/ferroptosis therapy for lung cancer.

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.

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.