Oxidative Stress In Tumor Cells Research Articles

Erucic acid increases the potency of cisplatin-induced colorectal cancer cell death and oxidative stress by upregulating the TRPM2 channel.

Erucic acid (ErA) is a source of omega-9 monounsaturated fatty acids. ErA exhibited antitumor effects by causing apoptosis and oxidative stress in tumor cells, with the exception of the HT-29 human colorectal cancer cell line. The apoptotic and Ca2+ signaling pathways in tumor cells are triggered when mitochondrial Ca2+ and Zn2+ accumulation produce reactive free oxygen species (ROS), which in turn activate TRPM2. ErA-induced ROS and TRPM2 stimulation may augment the anticancer action of cisplatin (CSP). We aimed to study the effects of ErA and CSP incubations on ROS, apoptosis, and cell death in the HT-29 cells by activating TRPM2. The cells were divided into five groups: control, ErA (200 µM for 48 h), CSP (25 µM for 24 h), and ErA + CSP + TRPM2 antagonists (200 µM carvacrol and 25 µM N-(p-amylcinnamoyl)anthranilic acid for 24 h). The TRPM2 antagonists reduced ErA plus CSP-induced increases in H2O2-induced intracellular free Ca2+ concentration ([Ca2+]c) and adenosine diphosphate-ribose-caused TRPM2 currents. ErA and CSP were found to cause apoptosis and cell death by raising the intracellular free Zn2+ concentration (Zn2+]c), caspase-3, -8, and -9, mitochondrial membrane dysfunction, and ROS, while lowering reduced glutathione, cell viability, and cell number. The oxidative, apoptotic, and tumor cell death effects of CSP in the cells were enhanced by the increase of ErA-mediated [Ca2+]c and Zn2+]c entering mitochondria through the activation of TRPM2. In conclusion, we observed that the combination of ErA and CSP was synergistic via TRPM2 activation for the treatment of HT-29 tumor cells.

Piezoelectric Bilayer Nickel-Iron Layered Double Hydroxide Nanosheets with Tumor Microenvironment Responsiveness for Intensive Piezocatalytic Therapy.

Piezocatalytic therapy (PCT) based on 2D layered materials has emerged as a promising non-invasive tumor treatment modality, offering superior advantages. However, a systematic investigation of PCT, particularly the mechanisms underlying the reactive oxygen species (ROS) generation by 2D nanomaterials, is still in its infancy. Here, for the first time, biodegradable piezoelectric 2D bilayer nickel-iron layered double hydroxide (NiFe-LDH) nanosheets (thickness of ≈1.86nm) are reported for enhanced PCT and ferroptosis. Under ultrasound irradiation, the piezoelectric semiconducting NiFe-LDH exhibits a remarkable ability to generate superoxide anion radicals, due to the formation of a built-in electric field that facilitates the separation of electrons and holes. Notably, the significant excitonic effect in the ultrathin NiFe-LDH system enables long-lived excited triplet excitons (lifetime of ≈5.04µs) to effectively convert triplet O2 molecules into singlet oxygen. Moreover, NiFe-LDH exhibited tumor microenvironment (TME)-responsive peroxidase (POD)-like and glutathione (GSH)-depleting capabilities, further enhancing oxidative stress in tumor cells and inducing ferroptosis. To the best of knowledge, this is the first report on piezoelectric semiconducting sonosensitizers based on LDHs for PCT and ferroptosis, providing a comprehensive understanding of the piezocatalysis mechanism and valuable references for the application of LDHs and other 2D materials in cancer therapy.

Catalytic activity of violet phosphorus-based nanosystems and the role of metabolites in tumor therapy.

Although nanocatalytic medicine has demonstrated its advantages in tumor therapy, the outcomes heavily relie on substrate concentration and the metabolic pathways are still indistinct. We discover that violet phosphorus quantum dots (VPQDs) can catalyze the production of reactive oxygen species(ROS) without requiring external stimuli and the catalytic substrates are confirmed to be oxygen (O2) and hydrogen peroxide (H2O2) through the computational simulation and experiments. Considering the short of O2 and H2O2 at the tumor site, we utilize calcium peroxide (CaO2) to supply catalytic substrates for VPQDs and construct nanoparticles together with them, named VPCaNPs. VPCaNPs can induce oxidative stress in tumor cells, particularly characterized by a significant increase in hydroxyl radicals and superoxide radicals, which cause substantial damage to the structure and function of cells, ultimately leading to cell apoptosis. Intriguingly, O2 provided by CaO2 can degrade VPQDs slowly, and the degradation product, phosphate, as well as CaO2-generated calcium ions, can promote tumor calcification. Antitumor immune activation and less metastasis are also observed in VPCaNPs administrated animals. In conclusion, our study unveils the anti-tumor activity of VPQDs as catalysts for generating cytotoxic ROS and the degradation products can promote tumor calcification, providing a promising strategy for treating tumors.

Nanomaterials Enhance Pyroptosis-Based Tumor Immunotherapy.

Pyroptosis, a pro-inflammatory and lytic programmed cell death pathway, possesses great potential for antitumor immunotherapy. By releasing cellular contents and a large number of pro-inflammatory factors, tumor cell pyroptosis can promote dendritic cell maturation, increase the intratumoral infiltration of cytotoxic T cells and natural killer cells, and reduce the number of immunosuppressive cells within the tumor. However, the efficient induction of pyroptosis and prevention of damage to normal tissues or cells is an urgent concern to be addressed. Recently, a wide variety of nanoplatforms have been designed to precisely trigger pyroptosis and activate the antitumor immune responses. This review provides an update on the progress in nanotechnology for enhancing pyroptosis-based tumor immunotherapy. Nanomaterials have shown great advantages in triggering pyroptosis by delivering pyroptosis initiators to tumors, increasing oxidative stress in tumor cells, and inducing intracellular osmotic pressure changes or ion imbalances. In addition, the challenges and future perspectives in this field are proposed to advance the clinical translation of pyroptosis-inducing nanomedicines.

A self-assembled theranostic nanoplatform for efficient tumor sonodynamic-gas therapy

The powerful antioxidant system in tumor tissues limits the efficacy of sonodynamic therapy (SDT) by reducing the availability of the produced reactive oxygen species (ROS). To address this problem, a pH/ultrasound (US) responsive theranostic nanoplatform is elaborately constructed by self-assembly of nitrogen-doped graphene quantum dots (NGQDs), benzothiazole sulfinate (BTS), Gd3+ ions and poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-PEG). The NGQD component with excellent sonodynamic activity wrapped in the resulting Gd-NGQDs/BTS@PLGA-PEG can efficaciously respond to ultrasonic irradiation and cause abundant ROS generation. Importantly, in response to acidic tumor microenvironment, the loaded BTS sustainably releases SO2, which induces the increase of intracellular •O2− level by inhibiting superoxide dismutase activity and further promotes the enrichment of ROS by reducing intracellular glutathione level and suppressing glutathione peroxidase 4 activity. The well-designed SO2 gas therapy-enhanced SDT strategy leads to high oxidative stress in tumor cells and effective inhibition of the growth of bilateral tumors with only a single intravenous injection of the nanomedicine and a subsequent single US irradiation. Gd-NGQDs/BTS@PLGA-PEG can also be employed as a good T1-weighted magnetic resonance imaging contrast agent to guide tumor therapy. This innovative therapeutic strategy developed in our contribution may provide a new paradigm for the exploration of deep tumor therapy.

Chelerythrine induces apoptosis and ferroptosis through Nrf2 in ovarian cancer cells.

Ovarian cancer is a prevalent malignancy in the female reproductive system, representing a significantly fatal and incurable tumor. Chelerythrine (CHE), a natural benzopyridine alkaloid, has demonstrated a broad spectrum of anticancer activities. Nevertheless, the ovarian cancer inhibitory impact of CHE remains unclear. In this study, we investigated the cytotoxic mechanism and potential targets of CHE on in vitro cultures of A2780 and SKOV3 cells derived from ovarian cancer. Additionally, in vivo experiments were conducted to confirm the suppressive impact of CHE on tumor growth in nude mice. The findings revealed that CHE impeded the growth of A2780 and SKOV3 cells in a concentration-time-dependent manner and significantly suppressed the development of tumors in nude mice. CHE elevated the level of oxidative stress in tumor cells, prompted cell cycle halt in the S phase, and increased their mitochondrial membrane potential. Western blotting results demonstrated that CHE could modulate the expression of proteins associated with apoptotic and ferroptosis processes in A2780 and SKOV3 cells. Nrf2 was verified to be an upstream key target mediating the inhibitory impact of CHE on ovarian cancer cells. In summary, CHE exerts its anti-cancer effects on ovarian cancer by modulating Nrf2, inhibiting cellular proliferation, and promoting apoptosis and ferroptosis.

Adjuvant Anti-tumor Therapy with Polyphenolic Compounds: A Review

Abstract: The search for effective methods of treatment and prevention of oncological diseases, despite the successes achieved in recent decades, remains one of the most urgent issues in modern medicine. It is known that chemotherapy and radiation therapy are based on the induction of cell death by increasing the intracellular concentration of reactive oxygen species (ROS). To increase the effectiveness of chemo- and radiotherapy, inducing and increasing oxidative stress in tumor cells has been proposed. A new class of promising adjuvants in combination with anticancer therapy, which has already been shown to be effective in preclinical and clinical studies, includes natural and synthetic polyphenols. Polyphenolic compounds not only exhibit antitumor activity but also significantly reduce the resistance of tumor cells to chemo- and radiotherapy. However, almost all chemotherapeutic drugs and regimens of radiation treatment have a damaging toxic effect on normal tissues, which significantly affects the quality of life of patients, and treatment options for managing these side effects are limited. In this regard, some of the most promising agents for the management of toxic side effects are natural polyphenols. This study discusses the possible molecular mechanisms and prospects for the clinical use of natural and synthetic polyphenolic compounds in chemo- and radiotherapy. In addition, the protective role/effect of polyphenols on the effects of chemoand radiotherapy in tumor patients is discussed.

A Novel Cu(II) Loaded Polypeptide SO2 Prodrug Nanoformulation Combining Chemodynamic and Gas Anticancer Therapies.

Sulfur dioxide (SO2)-based gas therapy and chemodynamic therapyare both reactive oxygen species (ROS)-mediated anticancer strategies, but there are few reports of their combined application. To this end, a novel graft-type copolymeric SO2 prodrug, PLG-g-mPEG-DNs, is designed and synthesized in this work. The amphiphilic polypeptides can self-assemble into nanoparticles (NPs) and encapsulated Cu(II) ions by metal-carboxyl coordination. In vitro release results showed that the obtained NPs-Cu can respond to the acidic pH and high glutathione levels typical of a tumor microenvironment to release Cu(II) and SO2 simultaneously. Both a Cu(II)-triggered Fenton-like reaction and the SO2 gas would promote ROS production and upregulate the oxidative stress in tumor cells, leading to an enhanced killing effect towards 4T1 cancer cells compared to either Cu(II) or the NPs alone. Furthermore, the in vitro hemolysis of NPs-Cu is less than 1.0% at a high concentration of 8mg/mL, indicating good blood compatibility and the potential for in vivo tumor inhibition application.

Mitochondrial transplantation inhibits cholangiocarcinoma cells growth by balancing oxidative stress tolerance through PTEN/PI3K/AKT signaling pathway

BackgroundCholangiocarcinoma (CCA) is a serious threat to human health, and tumor development is associated with abnormal mitochondrial function. It is believed that the introduction of healthy mitochondria into tumor cells can induce the oxidative stress in tumor cells to return to normal levels, thus exerting an inhibitory effect on tumor growth. MethodsMitochondria isolated from 143BρW cells were co-cultured with HuCCT1 cells, and the mitochondria were stained with MitoTracker dye as a tracking label. Changes in apoptosis, proliferation, oxidative stress, and PTEN/PI3K/AKT signaling pathway were assessed. In addition, a CCA nude mouse transplantation tumor model was constructed to analyze the effects of mitochondrial transplantation on the above factors in nude mice. Furthermore, the expression of PTEN was interfered to observe the effect and mechanism of mitochondrial transplantation on the proliferation and apoptosis of CCA cells. ResultsMitochondrial transplantation promoted apoptosis and inhibited cell proliferation in CCA cell line. SOD, GSH, and CAT activities were significantly increased, the expression of PTEN was activated, and the expression of p-PI3K and p-AKT were inhibited after mitochondrial transplantation. After mitochondrial transplantation + si-PTEN treatment, cell apoptosis, SOD, GSH, CAT activity, and the expression of PTEN were decreased, while the expression of p-PI3K and p-AKT were significantly enhanced. ConclusionThis study reveals the anti-tumor potential of mitochondrial transplantation through PTEN/PI3K/AKT signaling pathway to regulate cellular oxidative stress in CCA.

Remodeling of Tumor Microenvironment by Nanozyme Combined cGAS-STING Signaling Pathway Agonist for Enhancing Cancer Immunotherapy.

Nanozymes and cyclic GMP-AMP synthase (cGAS) the stimulator of interferon genes (STING) signaling pathway, as powerful organons, can remodel the tumor microenvironment (TME) to increase efficacy and overcome drug resistance in cancer immunotherapy. Nanozymes have the potential to manipulate the TME by producing reactive oxygen species (ROS), which lead to positive oxidative stress in tumor cells. Cyclic dinucleotide (2',3'-cGAMP), as a second messenger, exists in the TME and can regulate it to achieve antitumor activity. In this work, Co,N-doped carbon dots (CoNCDs) were used as a model nanozyme to evaluate the properties of the anti-tumor mechanism, and effective inhibition of S180 tumor was achieved. Based on CoNCDs' good biocompatibility and therapeutic effect on the tumor, we then introduced the cGAS-STING agonist, and the combination of the CoNCDs and STING agonist significantly inhibited tumor growth, and no significant systemic toxicity was observed. The combined system achieved the enhanced tumor synergistic immunotherapy through TME reprogramming via the peroxidase-like activity of the CoNCDs and cGAS-STING signaling pathway agonist synergistically. Our work provides not only a new effective way to reprogram TME in vivo, but also a promising synergic antitumor therapy strategy.

Doping Engineering to Modulate Lattice and Electronic Structure for Enhanced Piezocatalytic Therapy and Ferroptosis.

Piezocatalytic therapy, which generates reactive oxygen species (ROS) under mechanical force, has garnered extensive attention for its use in cancer therapy owing to its deep tissue penetration depth and less O2 -dependence. However, the piezocatalytic therapeutic efficiency is limited owing to the poor piezoresponse, low separation of electron-hole pairs, and complicated tumor microenvironment (TME). Herein, a biodegradable, porous Mn-doped ZnO (Mn-ZnO)nanocluster with enhanced piezoelectric effect is constructed via doping engineering. Mn-doping not only induces lattice distortion to increase polarization but also creates rich oxygen vacancies (OV ) for suppressing the recombination of electron-hole pairs, leading to high-efficiency generation of ROS under ultrasound irradiation. Moreover, Mn-doped ZnO shows TME-responsive multienzyme-mimicking activityandglutathione (GSH) depletion ability owing to the mixed valence of Mn (II/III), further aggravating oxidative stress. Density functional theory calculations show that Mn-doping can improve the piezocatalytic performance and enzyme activity of Mn-ZnO due to the presence of OV . Benefiting from the boosting of ROS generation and GSH depletion ability, Mn-ZnO can significantly accelerate the accumulation of lipid peroxide and inactivate glutathione peroxidase 4 (GPX4) to induce ferroptosis. The work may provide new guidance for exploring novel piezoelectric sonosensitizers for tumor therapy.

An Alternative Thinking in Tumor Therapeutics: Living Yeast Armored with Silicate.

A hybrid platform, constructed via the surface "armoring" of living yeasts by a manganese silicate compound (MS@Yeast), is investigated for combinational cancer treatment. The intrinsic characteristics of living yeasts, in both acidophilic and anaerobic conditions, empower the hybrid platform with activated selected colonization in tumors. While silicate particles are delivered in a targeting manner, yeast fermentation occurs at the cancerous region, inducing both alcohol and CO2. The excessive content of alcohol causes the hemangiectasis of tumor tissue, facilitating the penetration of therapeutics into central tumors and subsequent endocytosis. The catalytic Mn2+ ions, released from silicate particles, react with CO2 to induce forceful oxidative stress in tumor cells, ablating the primary tumors. More interestingly, the debris of sacrificed tumor cells and yeasts triggers considerable antitumor immune responses, rejecting both rechallenged and metastatic tumors. The integration of biologically active microorganisms and functional materials, illustrated in this study, provides distinctive perspectives in the exploration of potential therapeutics for tackling cancer.

Carbon nanoparticles-Fe(II) complex for efficient theranostics of xenografted colonic tumor

BackgroundOverwhelming Fe accumulation in tumor arouses strong oxidative stress. To benefit the cancer patients, Fe(II) delivered by carbon nanoparticles-Fe(II) complex (CNSI-Fe) should be visualized to ensure the successful intratumoral injection and the antitumor mechanisms should be investigated at molecular level.ResultsIntracellular Fe accumulations associating with the uptakes of CNSI-Fe were observed both in vitro and in vivo. The retention of Fe(II) in tumor over 72 h was visualized by magnetic resonance imaging. CNSI-Fe inhibited the tumor growth and expanded the lifespan of colonic tumor-bearing mice. The antitumor activity of CNSI-Fe was attributed to the increases of OH radicals and the oxidative stress in tumor cells, which resulted in cell apoptosis and ferroptosis. The transcriptome analyses confirmed the changes of ferroptosis and inflammation signaling pathways by CNSI-Fe treatment. The low toxicity of CNSI-Fe was indicated by the serum biochemistry, hematology, and histopathology.ConclusionCNSI-Fe induced the efficient apoptosis and ferroptosis of colonic tumor for cancer therapy. Our results would benefit the clinical applications of CNSI-Fe and stimulate great interest in the nanomedicine.

Redox and pH dual sensitive carboxymethyl chitosan functionalized polydopamine nanoparticles loaded with doxorubicin for tumor chemo-photothermal therapy

The high expression of reduced glutathione (GSH) and low pH in tumor sites have encouraged new ideas for targeted drug release. The tumor microenvironment is a crucial target for studying the anti-tumor efficiency of photothermal therapy because the microenvironment plays a key role in cancer progression, local resistance, immune escaping, and metastasis. Herein, active mesoporous polydopamine nanoparticles loaded with doxorubicin and functionalized with N,N′-bis(acryloyl)cystamine (BAC) and cross-linked carboxymethyl chitosan (CMC) were used to induce simultaneous redox- and pH-sensitive activity to achieve photothermal enhanced synergistic chemotherapy. The inherent disulfide bonds of BAC were able to deplete glutathione, thus increasing the oxidative stress in tumor cells and enhancing the release of doxorubicin. Additionally, the imine bonds between CMC and BAC were stimulated and decomposed in the acidic tumor microenvironment, improving the efficiency of light conversion through exposure to polydopamine. Moreover, in vitro and in vivo investigations demonstrated that this nanocomposite exhibited improved selective doxorubicin release in conditions mimicking the tumor microenvironment and low toxicity towards non-cancerous tissues, suggesting there is high potential for the clinical translation of this synergistic chemo-photothermal therapeutic agent.

Targeting self-enhanced ROS-responsive artesunatum prodrug nanoassembly potentiates gemcitabine activity by down-regulating CDA expression in cervical cancer

Prodrug self-delivery carriers with targeting that specifically responded to tumor microenvironments have good potential to improve the application dilemma of approved clinical therapeutic drugs (systemic distribution and side effects). It's noted the conversion of gemcitabine (GEM) to inactive ingredients under the action of cytidine deaminase (CDA) during metabolism in vivo limits its clinical effect. A high level of reactive oxygen species (ROS) results in a high level of oxidative stress in tumor cells, which changes the expression of CDA and optimizes the metabolism of GEM in vivo and overcome drug resistance. In this study, the ROS responsive and ROS self-supplied prodrug of artemisia (ART)-thioacetal bond (TK)-GEM was synthesized and self-vectors based on ART-TK-GEM (TK@FA NPs) was prepared by using nano precipitation. ROS responsive characteristics ensure specific release of prodrugs in tumor cells with high level of ROS thereby reducing side effects on normal cells and tissues. The endogenous ROS and newly generated ROS by ART can reduce the expression of CDA and optimizes the metabolism of GEM, and the accumulated ROS can also induce apoptosis of tumor cells, realizing synergistic anti-tumor effect of chemical drugs and traditional Chinese medicines. This paper proposes a simple method by using clinically approved drugs to improve the insufficient effect of existing chemotherapy and overcome resistance, which has potential to appropriately shorten the drug development cycle and accelerate the clinical investigation of drugs.

An implantable composite scaffold for amplified chemodynamic therapy and tissue regeneration.

Tissue regeneration and tumor cell killing after surgical resection are the two keys to achieving effective tumor therapy. In this study, an implantable system with combined functions of tumor therapy and tissue repair was constructed. Tannic acid (TA)/Fe3+ nanoparticles with Fenton catalytic activity were loaded with GSH inhibitor BSO drug (BTF), and acted as the therapeutic factor to realize amplified chemodynamic tumor treatment. Bioactive glass (BG) fibers loaded with vascular endothelial growth factor (VEGF) were used as the drug carrier matrix with tissue repair function (BGV). Then the BGV@BTF composite fibers were obtained by anchoring BTF nanoparticles on the surface of BGV fibers. Under tumorous acidic conditions, BTF nanoparticles can be released from the composite fibers, and taken up by tumor cells. Facilitated by BSO with the GSH suppression effect and TA with Fe3+ reducing properties, BTF nanoparticles can realize high oxidative stress in tumor cells and subsequent cell death. In addition, BG fibers and VEGF can both promote tissue regeneration and accelerate postoperative wound healing. The simultaneous suppression of tumor growth and promotion of tissue repair in this work is inspiring in the field of postoperative tumor treatment and recovery.

NIR-II Fluorescence Imaging-Guided Oxygen Self-Sufficient Nano-Platform for Precise Enhanced Photodynamic Therapy.

Tumor hypoxia and systemic toxicity seriously affect the efficacy of photodynamic therapy (PDT) and are considered as the "Achilles' heel" of PDT. Herein, to combat such limitations, an intelligent orthogonal emissions LDNP@SiO2 -CaO2 and folic acid-polyethylene glycol-Ce6 nanodrug is rationally designed and fabricated not only for relieving the hypoxic tumor microenvironment (TME) to enhance PDT efficacy, but also for determining the optimal triggering time through second near-infrared (NIR-II) fluorescence imaging. The designed nanodrug continuously releases a large amount of O2 , H2 O2 , and Ca2+ ions when exposed to the acidic TME. Meanwhile, under downshifting NIR-II bioimaging guidance, chlorine e6 (Ce6) consumes oxygen to produce 1 O2 upon excitation of upconversion photon. Moreover, cytotoxic reactive oxygen species (ROS) and calcium overload can induce mitochondria injury and thus enhance the oxidative stress in tumor cells. As a result, the NIR-II bioimaging guided TME-responsive oxygen self-sufficient PDT nanosystem presents enhanced anti-tumor efficacy without obvious systemic toxicity. Thus, the fabricated nanodrug offers great potential for designing an accurate cancer theranostic system.

Recent progress in cancer therapy based on the combination of ferroptosis with photodynamic therapy

Current anticancer treatments have many limitations to achieving high efficacy. Hence, novel strategies that broaden therapeutic prospects must urgently be developed. Ferroptosis is an iron-dependent form of non-apoptotic programmed cell death that is induced by cellular antioxidative system inhibition. Photodynamic therapy (PDT) uses photosensitizers to generate reactive oxygen species and aggravate oxidative stress in tumor cells. Combining ferroptosis with PDT cooperatively regulates intracellular redox homeostasis, thus increasing cancer cell susceptibility to oxidative stress and yielding synergistic anticancer effects. In this review, various strategies for combining ferroptosis with PDT are comprehensively summarized and discussed, including mono-PDT and PDT-induced ferroptosis, combining PDT with small-molecule ferroptosis inducers, and combining PDT with metal-ion-induced ferroptosis. Additionally, the possibility of combining ferroptosis and PDT with other anti-tumor therapies is discussed. Finally, the prospects and challenges of combining ferroptosis with PDT in clinical cancer treatment are addressed. With increased understanding of the superiority of combination PDT with ferroptosis for cancer treatment, we hope that drug delivery systems based on this strategy will be further developed to increase anticancer efficiency and achieve successful clinical translation.

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer. In agreement, the blanket use of NRF2 inducers or inhibitors along with anticancer therapies cause adverse effects in some preclinical cancer models. In this review, we have summarized the levels of oxidative stress, metabolic preferences and NRF2 activity in the different stages of prostate cancer. We also propose condition specific ways to use NRF2 inducers or inhibitors along with conventional prostate cancer therapies. The significance of this review is not only to provide a detailed understanding of the mechanism of action of NRF2 to regulate oxidative stress-mediated metabolic switching by prostate cancer cells to escape the radiation, chemo, or hormonal therapies, and to grow aggressively, but also to provide a potential therapeutic method to control aggressive prostate cancer growth by stage specific proper use of NRF2 regulators.

Dendritic Cu2+-Doped Ca2SiO4 Nanosphere for Cancer Therapy via Double Ion Interference

Ion interference therapy (IIT) is a promising cancer treatment strategy that can reverse ion distribution via bioactive nanomaterials so as to interfere with or hinder the physiological processes such as metabolism and proliferation of tumor cells. In this study, a dendritic Cu2+-doped calcium silicate nanosphere (Ca2SiO4) loaded with ruthenium red (RuR) and disulfiram (DSF) (RD-CCP) was constructed for self-enhanced chemodynamic therapy and IIT of tumors through the combination of Cu and Ca. Under the slightly acidic environment of the tumor, dendritic RD-CCP nanospheres (NPs) rapidly collapsed, and a toxic dithiocarbamate–Cu complex was generated in situ through the chelation reaction between DSF and the co-released Cu2+ ions. ROS accumulation was promoted by Fenton-like reaction between the Cu+ ions and the high level of H2O2 and glutathione. In addition, Ca2+-overload was promoted by the combination of the input of exogenous Ca2+ and the participation of RuR, which can inhibit the Ca2+ transport channel (MCU and SERCA), therefore promoting mitochondrial damage and enhancing oxidative stress in tumor cells. Furthermore, calcium transport channel imbalance caused by oxidative stress can promote tumor calcification and necrosis. In conclusion, dendritic RD-CCP NPs can simultaneously induce a Fenton-like response and a calcium-related signal imbalance at the tumor site through the double interference of Cu2+ and Ca2+, eventually leading to rapid tumor apoptosis, which has great application potential in the clinical application of tumor therapy.