bims-rehoca 2021-09-26 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021‒09‒26
twenty-five papers selected by
Vittoria Raimondi
Veneto Institute of Oncology

Implications of reactive oxygen species on cancer formation and its treatment.
Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy.
Carboxymethyl dextran-based nanocomposites for enhanced chemo-sonodynamic therapy of cancer.
Anticancer agents based on Plastoquinone analogs with N-phenylpiperazine: Structure-activity relationship and mechanism of action in breast cancer cells.
Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy.
Methionine restriction exposes a targetable redox vulnerability of triple-negative breast cancer cells by inducing thioredoxin reductase.
Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers TXNIP expression.
Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.
Induction of immunogenic cell death in cancer cells by a photoactivated platinum(IV) prodrug.
Ubiquilin 1 suppresses the cancer stem cell-like traits of non-small cell lung cancer cells by regulating reactive oxygen species homeostasis.
Brg1 mutation alters oxidative stress responses in glioblastoma.
Significance of glutathione peroxidase 4 and intracellular iron level in ovarian cancer cells-"utilization" of ferroptosis mechanism.
Both-In-One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem-Amplifying Reactive Oxygen Species-Immunity Responses.
Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy.
Icaritin induces cellular senescence by accumulating the ROS production and regulation of the Jak2/Stat3/p21 pathway in imatinib-resistant, chronic myeloid leukemia cells.
Acrylamide induces intrinsic apoptosis and inhibits protective autophagy via the ROS mediated mitochondrial dysfunction pathway in U87-MG cells.
Suppressing TRAP1 sensitizes glioblastoma multiforme cells to temozolomide.
Mesoporous polydopamine-coated hydroxyapatite nano-composites for ROS-triggered nitric oxide-enhanced photothermal therapy of osteosarcoma.
Engineering Paclitaxel Prodrug Nanoparticles via Redox-Activatable Linkage and Effective Carriers for Enhanced Chemotherapy.
A mitochondrion-targeted BODIPY-Ir(III) conjugate as a photoinduced ROS generator for the oxidative destruction of triple-negative breast cancer cells.
A flowerlike FePt/MnO2/GOx-based cascade nanoreactor with sustainable O2 supply for synergistic starvation-chemodynamic anticancer therapy.
THIOL-BASED ANTIOXIDANTS AND THE EPITHELIAL-MESENCHYMAL TRANSITION IN CANCER.
Potent Nrf2-inducing, antioxidant, and anti-inflammatory effects and identification of constituents validate the anti-cancer use of Uvaria chamae and Olax subscorpioidea.
A nonferrous ferroptosis-like strategy for antioxidant inhibition-synergized nanocatalytic tumor therapeutics.
Fenton Reaction Induced by Fe-Based Nanoparticles for Tumor Therapy.

Semin Oncol. 2021 Aug 04. pii: S0093-7754(21)00051-8. [Epub ahead of print]

Implications of reactive oxygen species on cancer formation and its treatment.

Manish A Shah, Harry A Rogoff.

  Elevated levels of reactive oxygen species (ROS) are a hallmark of cancer. Although increased ROS concentrations play important roles in cancer formation and progression, levels above a cytotoxic threshold cause cancer cell death. Cancer cells adapt to high concentrations of ROS via antioxidant production and reprogrammed cellular metabolism (eg, the Warburg effect). Because some widely used anticancer therapies such as radiation therapy and chemotherapy rely on ROS accumulation as a mechanism to induce cancer cell death, a cancer cell's ability to control ROS levels is a driver of treatment resistance and a critical consideration for successful cancer treatment. The necessity for cancer cells to adapt to elevated levels of ROS to survive may represent an Achilles heel for some malignancies, as therapies designed to interfere with this adaptation would be expected to kill cancer cells. In this review, we provide an overview of the implications of ROS on cancer formation and anticancer treatment strategies, with a focus on treatment-resistant disease.

Keywords:  cancer; drug resistance; reactive oxygen species; reduction-oxidation balance; treatment

DOI:  https://doi.org/10.1053/j.seminoncol.2021.05.002
Oxid Med Cell Longev. 2021 ;2021 8532940

Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy.

Jiabing Wang, Dongsheng Sun, Lili Huang, Shijian Wang, Yong Jin.

Accumulating evidence shows that elevated levels of reactive oxygen species (ROS) are associated with cancer initiation, growth, and response to therapies. As concentrations increase, ROS influence cancer development in a paradoxical way, either triggering tumorigenesis and supporting the proliferation of cancer cells at moderate levels of ROS or causing cancer cell death at high levels of ROS. Thus, ROS can be considered an attractive target for therapy of cancer and two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to treat cancer. Despite tremendous resources being invested in prevention and treatment for cancer, cancer remains a leading cause of human deaths and brings a heavy burden to humans worldwide. Chemotherapy remains the key treatment for cancer therapy, but it produces harmful side effects. Meanwhile, the process of de novo development of new anticancer drugs generally needs increasing cost, long development cycle, and high risk of failure. The use of ROS-based repurposed drugs may be one of the promising ways to overcome current cancer treatment challenges. In this review, we briefly introduce the source and regulation of ROS and then focus on the status of repurposed drugs based on ROS regulation for cancer therapy and propose the challenges and direction of ROS-mediated cancer treatment.

DOI: https://doi.org/10.1155/2021/8532940
Carbohydr Polym. 2021 Dec 01. pii: S0144-8617(21)00875-4. [Epub ahead of print]273 118488

Carboxymethyl dextran-based nanocomposites for enhanced chemo-sonodynamic therapy of cancer.

Wooram Um, Pramod Kumar E K, Yeari Song, Jeongjin Lee, Jae Yoon An, Hyeyeon Joo, Dong Gil You, Jae Hyung Park.

  Glutathione (GSH), a tripeptide abundant in the cancer cells, inhibits the cytotoxic effect of reactive oxygen species (ROS) and is associated with anti-apoptosis, thus facilitating tumor growth. Here, we report GSH-depleting carboxymethyl dextran nanocomposites for chemo-sonodynamic therapy for cancer. The nanocomposite is composed of the TiO2-based core as the sonosensitizer, MnO2 coat as the GSH-consuming chemosensitizer, and carboxymethyl dextran as the hydrophilic shell. The in vitro cell experiments demonstrated that, when taken up by the cancer cells, the nanocomposites can deplete intracellular GSH by reducing MnO2 to Mn2+ which induces intracellular ROS production. Upon exposure to ultrasound, the nanocomposites effectively generated cytotoxic singlet oxygen at the intracellular level, remarkably enhancing the cytotoxicity to cancer cells. Notably, chemo-sonodynamic activity of the nanocomposites induced apoptosis as well as necrosis of cancer cells, implying their high potential as the anticancer therapeutics.

Keywords:  Cancer therapy; Carboxymethyl dextran; Glutathione; Nanoparticles; Sonodynamic therapy

DOI:  https://doi.org/10.1016/j.carbpol.2021.118488
Chem Biol Interact. 2021 Sep 21. pii: S0009-2797(21)00311-2. [Epub ahead of print] 109673

Anticancer agents based on Plastoquinone analogs with N-phenylpiperazine: Structure-activity relationship and mechanism of action in breast cancer cells.

Ayse Tarbin Jannuzzi, Mahmut Yıldız, Nilüfer Bayrak, Hatice Yıldırım, Deepak Shilkar, Venkatesan Jayaprakash, Amaç Fatih Tuyun.

  2,3-Dimethyl-1,4-benzoquinones named as Plastoquinone (PQ) analogs have antiproliferative activity and are promising new members of molecules that can be used to cope with cancer. In an attempt to develop effective and potentially safe antiproliferative agents, previously reported twelve Plastoquinone analogs (PQ1-12) have been obtained to understand their antiproliferative profile. All PQ analogs have been selected by the National Cancer Institute (NCI) of Bethesda based on the NCI Developmental Therapeutics Program and tested against the panel of 60 cancer cell lines. Based on those studies, the cytotoxicity of the selected PQ analogs (PQ8, PQ9, PQ11, and PQ12) was determined using four breast cancer cell lines (MCF7, UACC-2087, MDA-MB-231, and MDA-MB-435) and a normal cell line (HaCaT). For better understanding, apoptosis induction, changes in cell proliferation, cell migration, and reactive oxygen species (ROS) generation were investigated for the selected PQ analog on MCF7 and UACC-2087 cell lines. According to the study results, PQ11 showed the most promising anticancer activity against MCF7 cell line through increased oxidative stress and apoptosis and suppression of cell proliferation. Based on the biological activity profile, we hypothesize that PQ11 could be a modulator of the cannabinoid 2 (CB2) receptor. Accordingly, we analyzed molecular level interaction of PQ11 with CB2 receptor through molecular docking simulation and it was also predicted to have a favorable ADMET profile. Overall, our findings suggest that integration of the N-phenylpiperazine moiety can be a good strategy for the structural optimization of PQ analogs as anticancer agents, especially in breast cancer.

Keywords:  Aminoquinone; Anticancer activity; Breast cancer; Cytotoxicity; Molecular docking; Oxidative stress; Plastoquinones; ROS generation

DOI:  https://doi.org/10.1016/j.cbi.2021.109673
Biomaterials. 2021 Sep 11. pii: S0142-9612(21)00485-3. [Epub ahead of print]277 121128

Reactive oxygen species-activatable self-amplifying Watson-Crick base pairing-inspired supramolecular nanoprodrug for tumor-specific therapy.

Xiaoyu Xu, Zishan Zeng, Xin Ding, Ting Shan, Qiuxing Liu, Meixu Chen, Jie Chen, Meng Xia, Yuanfeng He, Zeqian Huang, Yanjuan Huang, Chunshun Zhao.

  Intratumoral upregulated reactive oxygen species (ROS) has been extensively exploited as exclusive stimulus to activate drug release for tumor-specific therapy. However, insufficient endogenous ROS and tumor heterogeneity severely restrict clinical translation of current ROS-responsive drug delivery systems. Herein, a tailored ROS-activatable self-amplifying supramolecular nanoprodrug was developed for reinforced ROS-responsiveness and highly selective antitumor therapy. A novel ROS-cleavable CA-based thioacetal linker CASOH was synthesized with ROS generator cinnamaldehyde (CA) incorporated into its molecular structure, to skillfully realize self-amplifying positive feedback loop of "ROS-activated CA release with CA-induced ROS regeneration". CASOH was modified with a cytosine analogue gemcitabine (GEM) to obtain ROS-activatable self-immolative prodrug CAG, which could be selectively activated in tumor cells and further achieve self-boosting "snowballing" activation via ROS compensation, while keep inactive in normal cells. Through Watson-Crick nucleobase pairing (G≡C)-like hydrogen bonds, CAG efficiently crosslinked with a matched guanine-rich acyclovir-modified hyaluronic acid conjugate HA-ACV, to self-assemble into pH/ROS dual-responsive supramolecular nanoprodrug HCAG. With high stability, beneficial tumor targeting capacity and pH/ROS-responsiveness, HCAG nanoformulation exhibited remarkable in vivo antitumor efficacy with minimal systemic toxicity. Based on unique tumor-specific self-amplifying prodrug activation and Watson-Crick base pairing-inspired supramolecular self-assembly, this study provides an inspirational strategy of exploiting novel ROS-responsive nanoplatform with reinforced responsiveness and specificity for future clinical translation.

Keywords:  Hydrogen bonds; Reactive oxygen species; Self-amplifying; Supramolecular nanoprodrug; Tumor-specific therapy

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121128
Breast Cancer Res Treat. 2021 Sep 22.

Methionine restriction exposes a targetable redox vulnerability of triple-negative breast cancer cells by inducing thioredoxin reductase.

Dmitry Malin, Yoonkyu Lee, Olga Chepikova, Elena Strekalova, Alexis Carlson, Vincent L Cryns.

  PURPOSE: Tumor cells are dependent on the glutathione and thioredoxin antioxidant pathways to survive oxidative stress. Since the essential amino acid methionine is converted to glutathione, we hypothesized that methionine restriction (MR) would deplete glutathione and render tumors dependent on the thioredoxin pathway and its rate-limiting enzyme thioredoxin reductase (TXNRD).METHODS: Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control or MR media and the effects on reactive oxygen species (ROS) and antioxidant signaling were examined. To determine the role of TXNRD in MR-induced cell death, TXNRD1 was inhibited by RNAi or the pan-TXNRD inhibitor auranofin, an antirheumatic agent. Metastatic and PDX TNBC mouse models were utilized to evaluate in vivo antitumor activity.
RESULTS: MR rapidly and transiently increased ROS, depleted glutathione, and decreased the ratio of reduced glutathione/oxidized glutathione in TNBC cells. TXNRD1 mRNA and protein levels were induced by MR via a ROS-dependent mechanism mediated by the transcriptional regulators NRF2 and ATF4. MR dramatically sensitized TNBC cells to TXNRD1 silencing and the TXNRD inhibitor auranofin, as determined by crystal violet staining and caspase activity; these effects were suppressed by the antioxidant N-acetylcysteine. H-Ras-transformed MCF-10A cells, but not untransformed MCF-10A cells, were highly sensitive to the combination of auranofin and MR. Furthermore, dietary MR induced TXNRD1 expression in mammary tumors and enhanced the antitumor effects of auranofin in metastatic and PDX TNBC murine models.
CONCLUSION: MR exposes a vulnerability of TNBC cells to the TXNRD inhibitor auranofin by increasing expression of its molecular target and creating a dependency on the thioredoxin pathway.

Keywords:  Auranofin; Cancer; Glutathione; Methionine; Nutrition; Oxidative stress; Thioredoxin

DOI:  https://doi.org/10.1007/s10549-021-06398-y
Free Radic Biol Med. 2021 Sep 18. pii: S0891-5849(21)00725-5. [Epub ahead of print]

Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers TXNIP expression.

Ola Karmi, Yang-Sung Sohn, Sara I Zandalinas, Linda Rowland, Skylar King, Rachel Nechushtai, Ron Mittler.

  The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and neurodegenerative diseases. It was found to control different calcium, reactive oxygen species (ROS), and iron signaling mechanisms. However, since most studies of CISD2 to date were conducted with cells that constitutively lack, overexpress, or contain mutations in CISD2, the relationships between these different signaling processes are unclear. To address the hierarchy of signaling events occurring in cells upon CISD2 disruption, we developed an inducible system to express CISD2, or the dominant-negative H114C inhibitor of CISD2, in human breast cancer cells. Here, we report that inducible disruption of CISD2 function causes an immediate disruption in mitochondrial labile iron (mLI), and that this disruption results in enhanced mitochondrial ROS (mROS) levels. We further show that alterations in cytosolic and ER calcium levels occur only after the changes in mLI and mROS levels happen and are unrelated to them. Interestingly, disrupting CISD2 function resulted in the enhanced expression of the tumor suppressor thioredoxin-interacting protein (TXNIP) that was dependent on the accumulation of mLI and associated with ferroptosis activation. CISD2 could therefore regulate the expression of TXNIP in cancer cells, and this regulation is dependent on alterations in mLI levels.

Keywords:  CISD2; Cancer; Ferroptosis; Iron homeostasis; Iron-sulfur cluster [Fe–S]; Mitochondria; NAF-1; Oxidative stress; Reactive oxygen species (ROS); TXNIP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.013
Biomed Pharmacother. 2021 Sep 15. pii: S0753-3322(21)00926-4. [Epub ahead of print]143 112142

Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.

Abdul Q Khan, Khalid Rashid, Abdulhadi A AlAmodi, Maha Victor Agha, Sabah Akhtar, Ishrat Hakeem, Syed Shadab Raza, Shahab Uddin.

  Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.

Keywords:  Benzophenanthridine alkaloids; Cancer; Cancer stemness; Natural products; Oxidative stress; ROS

DOI:  https://doi.org/10.1016/j.biopha.2021.112142
Inorg Chem Front. 2020 Sep 18. 7 4150-4159

Induction of immunogenic cell death in cancer cells by a photoactivated platinum(IV) prodrug.

Vojtech Novohradsky, Jitka Pracharova, Jana Kasparkova, Cinzia Imberti, Hannah E Bridgewater, Peter J Sadler, Viktor Brabec.

The platinum(IV) prodrug trans,trans,trans-[Pt(N3)2(OH)2(py)2] (1) is stable and non-toxic in the dark, but potently cytotoxic to cancer cells when irradiated by visible light, including cisplatin-resistant cells. On irradiation with visible light, it generates reactive Pt(II) species which can attack DNA, and produces reactive oxygen species (ROS) and reactive nitrogen species (RNS) which exert unusual effects on biochemical pathways. We now show that its novel mechanism of action includes induction of immunogenic cell death (ICD). Treatment of cancer cells with 1 followed by photoirradiation with visible light induces calreticulin (CRT) expression at the surface of dying cancer cells. This is accompanied by release of high mobility group protein-1B (HMGB1) and the secretion of ATP. Autophagy appears to play a key role in this chemotherapeutically-stimulated ICD. The observed uneven distribution of ecto-CRT promotes phagocytosis, confirmed by the observation of engulfment of photoirradiated CT26 colorectal cancer cells treated with 1 by J774.A1 macrophages. The photoactivatable prodrug 1 has a unique mechanism of action which distinguishes it from other platinum drugs due to its immunomodulating properties, which may enhance its anticancer efficacy.

DOI: https://doi.org/10.1039/d0qi00991a
Bioengineered. 2021 Dec;12(1): 7143-7155

Ubiquilin 1 suppresses the cancer stem cell-like traits of non-small cell lung cancer cells by regulating reactive oxygen species homeostasis.

Ting Liu, Qianqian Ma, Wenjie Li, Yan Hu, Jun Yang, Qi Yao.

  Cancer stem cell (CSC) has been confirmed to trigger tumor occurrence and progression and CSC can develop strategies to maintain a lower reactive oxygen species (ROS) level compared to cancer cells. However, the mechanisms contributing to ROS homeostasis in CSC are still lacking key elements. In the current study, we found that reductive redox states and ROS levels were suppressed in non-adherent spheres formed by non-small cell lung cancer (NSCLC) cells, which were confirmed to hold CSC-like traits. However, mitochondria DNA content and cellular oxygen consumption rate analyses revealed fewer numbers of mitochondria in NSCLC spheres. Further exploration attributed this result to decreased mitochondrial biogenesis, likely resulted from the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Mechanistic studies indicated that Ubiquilin 1 (UBQLN1) increased PGC1α protein stability via reducing the ubiquitination of PGC1α protein. Moreover, UBQLN1 was lowly expressed in NSCLC spheres compared to that in parental NSCLC cells and UBQLN1 overexpression suppressed the CSC-like traits of NSCLC cells, which was characterized as the decrease of ALDH1 activity, sphere-formation ability, and CSC marker expression. Finally, clinical investigations further demonstrated that UBQLN1 level was positively correlated with patient's survival of lung adenocarcinoma, but not squamous cell carcinoma of lung. Taken together, our results revealed a novel mechanism involving ROS homeostasis and mitochondrial biogenesis in non-small cell lung CSCs, which may provide novel potential targets and methods for NSCLC patients.

Keywords:  PGC1α; UBQLN1; cancer stem cell; mitochondrial biogenesis; reactive oxygen species

DOI:  https://doi.org/10.1080/21655979.2021.1979353
Neurochem Int. 2021 Sep 17. pii: S0197-0186(21)00235-7. [Epub ahead of print] 105189

Brg1 mutation alters oxidative stress responses in glioblastoma.

Pruthvi Gowda, Kirti Lathoria, Sonia B Umdor, Ellora Sen.

  Increasing evidences suggest that the SWI/SNF chromatin remodeling complex involved in organization of chromatin architecture via ATP hydrolysis, play important role in human cancer. As TCGA gene expression analyses revealed signature of enhanced oxidative stress in GBMs harbouring Brg1mutations, we examined the involvement of ATPase subunit of BRG1 in regulating oxidative stress responses in glioma. BRG1-MUT overexpressing glioma cells exhibit intrinsically higher reactive oxygen species (ROS) levels as compared to BRG1-WT. Elevated ROS generation was concomitant with decreased expression of NF-E2- related factor 2 (NRF2), superoxide dismutases (SOD-1,2) and thioredoxins (TrX-1,2). A similar change in redox regulatory genes and ROS production was observed upon siRNA-mediated knockdown of Brg1. Increased sensitivity to temozolomide was observed upon loss of BRG1-ATPase catalytic domain. These findings highlight the role of ATPase domain of BRG1 in regulating redox homeostasis and sensitivity to oxidative stressors in glioma cells. BRG1 mutation created vulnerability to elevated ROS levels can be therapeutically exploited, with ROS stressors as a promising therapeutic target for the treatment of BRG1-mutant cancers.

Keywords:  BRG1; ROS; Temozolomide

DOI:  https://doi.org/10.1016/j.neuint.2021.105189
Inflamm Res. 2021 Sep 19.

Significance of glutathione peroxidase 4 and intracellular iron level in ovarian cancer cells-"utilization" of ferroptosis mechanism.

Dingxi Li, Mengli Zhang, Hongtu Chao.

  OBJECTIVE AND DESIGN: Ovarian cancer is the major cause of death in gynecologic diseases worldwide. Ferroptosis, a nonapoptotic form of cell death, is featured by accumulation of iron-based lipid peroxidation. The elevated iron level and malondialdehyde (MDA) in ovarian cancer cells suggest more vulnerable to ferroptosis, nevertheless, ferroptosis is not observed in ovarian cancer cells. Glutathione peroxidase 4 (GPX4) is a critical regulator of ferroptosis.METHODS: We determined whether GPX4 knockdown could induce ferroptosis to prevent cell proliferation in ovarian cancer. Human ovarian cancer cells and normal human ovarian epithelial cell line IOSE-80 were cultured and administrated with deferoxamine (DFO) or ferric ammonium citrate (FAC). GPX4 knockdown was established for investigating the functions of GPX4 in ovarian cancer cells and in tumor xenograft mice.
RESULTS: A positively correlation was showed among the levels of GPX4, iron and cell proliferation. Chelation of intracellular iron by DFO disrupted intracellular iron level and was detrimental to ovarian cancer cell survival. FAC-induced elevation of intracellular iron inhibited proliferation, aggravated apoptosis, boosted inflammation and suppressed lipid peroxide reducibility in ovarian cancer cells. Knockdown of GPX4 had similar effects with FAC in ovarian cancer cells. Inhibition of GPX4 suppressed tumor growth, induced ferroptosis, accelerated cell apoptosis, reduced Fe3+ accumulation and suppressed lipid peroxide reducibility in tumor bearing mice.
CONCLUSION: We demonstrate the significance of GPX4 and intracellular iron level in ovarian cancer cells. Importantly, inhibition of GPX4 interferes with both intracellular iron homeostasis and lipid peroxide reducibility, inducing ferroptosis and exerting anti-cancer effect, which can be a potential effective strategy for ovarian cancer therapy.

Keywords:  Ferroptosis; Glutathione peroxidase 4; Iron; Malondialdehyde; Ovarian cancer

DOI:  https://doi.org/10.1007/s00011-021-01495-6
Adv Healthc Mater. 2021 Sep 20. e2100950

Both-In-One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem-Amplifying Reactive Oxygen Species-Immunity Responses.

Mengchi Sun, Hao Ye, Qinghua Shi, Jun Xie, Xiang Yu, Hao Ling, Song You, Zhonggui He, Bin Qin, Jin Sun.

  Bacterial therapy, which targets the tumor site and aims at exerting an antitumor immune response, has displayed a great potential against malignant tumors. However, failure of the phase I clinical trial of Salmonella strain VNP20009 alone demonstrates that bacterial treatment alone can unsatisfy the requirements of high efficiency and biosafety. Herein, a strategy of both-in-one hybrid bacteria is proposed, wherein the chemotherapeutic drug doxorubicin (DOX) is integrated onto the surface of glucose dehydrogenase (GDH)-overexpressed non-pathogenic Escherichia coli (E. coli) strain, to potentiate the antitumor efficacy. Nicotinamide adenine dinucleotide phosphate (NADPH), which is produced by GDH from E. coli, promotes the generation of toxic reactive oxygen species (ROS) within the tumor, and ROS is then catalyzed by the DOX-activated NADPH oxidases. Importantly, the hybrid bacteria enhance stimulated systemic antitumor immune responses, thereby leading to effective tumor eradication. When this strategy is applied in four different tumor models, the hybrid bacteria significantly inhibited tumor metastasis, postsurgical regrowth, and primary/distal tumor relapse. The both-in-one ROS-immunity-boosted hybrid bacteria strategy provides knowledge for the rational design of bacteria-based synergistic cancer therapy.

Keywords:  both-in-one hybrid bacteria; non-pathogenic Escherichia coli strain; reactive oxygen species-immunity-boosted; synergistic cancer therapy; toxic reactive oxygen species

DOI:  https://doi.org/10.1002/adhm.202100950
J Cancer. 2021 ;12(20): 6198-6208

Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy.

Yanjuan He, Duanfeng Jiang, Kaixuan Zhang, Yinghong Zhu, Jingyu Zhang, Xuan Wu, Jiliang Xia, Yan Zhu, Lang Zou, Jian Hu, Yajuan Cui, Wen Zhou, Fangping Chen.

  Drug resistance is the major cause for disease relapse and patient death in multiple myeloma (MM). It is an urgent need to develop new therapies to overcome drug resistance in MM. Chidamide (CHI), a novel oral HDAC inhibitor targeting HDAC1, 2, 3 and 10, has shown potential therapeutic effect in MM. In this study, we determined that CHI exhibited significant anti-tumor effect on MM cells both in vitro and in vivo, which was positively correlated with the expression of HDAC1. Meanwhile, CHI enhanced Bortezomib (BTZ) effects synergistically in MM cells and a combination of CHI with BTZ induced myeloma cell apoptosis and G0/G1 arrest in vitro and in vivo. Mechanistically, the synergistic anti-tumor effect of CHI and BTZ was related with the increased production of reactive oxygen species (ROS) dependent DNA damage and the changes of cell apoptosis and cycle pathways. Our data indicate that CHI may be a suitable drug to sensitize BTZ in MM cells, which provides novel insight into the therapy for MM patients.

Keywords:  Bortezomib; Chidamide; Multiple myeloma; Reactive oxygen species

DOI:  https://doi.org/10.7150/jca.61602
Am J Transl Res. 2021 ;13(8): 8860-8872

Icaritin induces cellular senescence by accumulating the ROS production and regulation of the Jak2/Stat3/p21 pathway in imatinib-resistant, chronic myeloid leukemia cells.

Shicong Zhu, Cheng Xing, Guangsen Zhang, Hongling Peng, Zhihua Wang.

In patients with chronic myelogenous leukemia (CML), resistance to tyrosine kinase inhibitor (TKI) therapy, like imatinib, can cause death, progression to accelerated phase or blast crises, and the need for maintenance treatment. Icaritin is an active component of the genus Epimedium, a traditional Chinese herbal medicine. Icaritin has been shown to notably inhibit the growth of CML cells. To explore the potential mechanisms of inhibiting growth and inducing cell senescence in imatinib-resistant CML cells by icaritin, MTT assays were used to assess the cell viability. The apoptosis and cell cycle arrest were evaluated using flow cytometry. The SA-β-Gal staining and the intracellular reactive oxygen species (ROS) production were measured using flow cytometry to detect the senescent cells. qRT-PCR was conducted to assess the expression of the cell cycle-associated proteins, and western blotting was used to analyze the expressions of the JAK2 and STAT3 phosphorylation proteins. The results showed that icaritin inhibited cell growth and induced cell senescence in imatinib-resistant CML cells, which is associated with the regulation of the JAK2/STAT3/P21 axis and accompanied by the accumulation of ROS. Our data suggest that icaritin is a promising therapeutic strategy for the treatment of imatinib-resistant patients with CML.

Keywords: Icaritin; Jak2/Stat3/p21 pathway; imatinib-resistant chronic myeloid leukemia; reactive oxygen species; senescence
Drug Chem Toxicol. 2021 Sep 22. 1-12

Acrylamide induces intrinsic apoptosis and inhibits protective autophagy via the ROS mediated mitochondrial dysfunction pathway in U87-MG cells.

Linlin Deng, Mengyao Zhao, Yanan Cui, Quanming Xia, Lihua Jiang, Hao Yin, Liming Zhao.

  Acrylamide (ACR) is a potential neurotoxin commonly found in the environment, as well as in food repeatedly exposed heat processing, but the mechanism underpinning ACR-induced neurotoxicity remains unclear. This study investigated the potential association and underlying signal transduction of oxidative stress, apoptosis, and autophagy associated with ACR-triggered neurotoxicity. Therefore, U87-MG cells were treated with varying ACR concentrations, while the cell activity reduction depended on the specific dosage and time parameters. Biochemical analyses showed that ACR significantly increased the reactive oxygen species (ROS), malondialdehyde (MDA), and Ca2+ levels while decreasing the glutathione (GSH) levels and mitochondrial membrane potential (ΔΨm), finally leading to a higher cell apoptotic rate. Moreover, ACR induced U87-MG cell apoptosis and autophagy via ROS-triggered expression in the mitochondrial apoptosis pathway, NF-κB activation, and autophagosome accumulation. In addition, the autophagosome accumulation induced by ACR could probably be ascribed to blocked autophagic flux, inhibiting the autophagosomes from combining with lysosomes, while the inhibition of autophagy caused by ACR further promoted the initiation of apoptosis. In conclusion, the results indicated that the apoptotic and autophagic pathways responded to ACR-induced neurotoxicity. However, inhibited protective autophagy further promoted apoptotic progression. New insights may be derived from these cellular responses that can help develop diverse pathway strategies for assessing the risk posed by ACR.HIGHLIGHTSACR induced mitochondrial- and caspase-dependent apoptosis in U87-MG cells.ACR regulated the autophagic markers and blocked autophagic flux in U87-MG cells.ACR inhibited protective autophagy and promoted apoptotic initiation in U87-MG cells.

Keywords:  Acrylamide; NF-κB activation; intrinsic apoptosis; oxidative stress; protective autophagy

DOI:  https://doi.org/10.1080/01480545.2021.1979030
Exp Ther Med. 2021 Nov;22(5): 1246

Suppressing TRAP1 sensitizes glioblastoma multiforme cells to temozolomide.

Nan Wang, Peining Zhu, Renxuan Huang, Liankun Sun, Delu Dong, Yufei Gao.

  Glioma is a common malignant tumor of the central nervous system, accounting for ~50% of intracranial tumors. The current standard therapy for glioma is surgical resection followed by postoperative adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. However, resistance to TMZ is one of the factors affecting prognosis. It has been reported that TNF receptor-associated protein 1 (TRAP1) is overexpressed in numerous types of tumor and that interfering with its function may abrogate chemotherapy resistance. TRAP1 inhibitor Gamitrinib triphenylphosphonium (G-TPP) and shRNA were used in the present study to suppress the function of this molecule in glioblastoma multiforme (GBM) cell lines. MTT assay was performed to evaluate the combined effect of G-TPP and TMZ treatment. To investigate the underlying mechanism responsible for this combined effect, the mitochondrial unfolded protein response (mtUPR), mitophagy, mitochondrial fusion and reactive oxygen species (ROS) were quantified using western blotting and immunofluorescence techniques. TMZ treatment induced apoptosis in GBM cells by activating the p53 pathway, whilst simultaneously downregulating mitophagy and enhancing mitochondrial fusion. The latter may occur in order to compensate for the defect caused by downregulated mitophagy. Suppressing the function of TRAP1 disturbed this compensatory mechanism by inducing mtUPR, which resulted in a burst of ROS formation and sensitized the GBM cells to the effects of TMZ treatment. Thus, suppressing the function of TRAP1 sensitized GBM cells to TMZ lysis by inducing mtUPR and the subsequent ROS burst. TRAP1 is therefore considered to be a promising target for GBM therapy.

Keywords:  TNF receptor-associated protein 1; glioblastoma multiforme; mitochondrial unfolded protein response; reactive oxygen species; temozolomide

DOI:  https://doi.org/10.3892/etm.2021.10681
J Mater Chem B. 2021 Sep 22. 9(36): 7401-7408

Mesoporous polydopamine-coated hydroxyapatite nano-composites for ROS-triggered nitric oxide-enhanced photothermal therapy of osteosarcoma.

Yong-Chao Wang, Hong-Lian Dai, Ze-Hao Li, Zhi-Yuan Meng, Yao Xiao, Zheng Zhao.

In this paper, MPDA@hydroxyapatite nanocomposites (MPHA NCs) were prepared and applied to develop a novel reactive oxygen species (ROS)-triggered nitric oxide (NO)-enhanced photothermal therapy nanocomposite system composed of indocyanine green (ICG)/L-arginine-MPDA@HAp (AI-MPHA NCs) for displaying both NO gas therapy and photothermal osteosarcoma treatment. The nanosystem exhibited a mesoporous and core-shell structure and high ICG loading efficiency (about 90%). Under near infrared (NIR) irradiation, the AI-MPHA NCs could not only produce heat but also generate reactive oxygen species (ROS), inducing the catalysis of L-Arg to obtain NO. Under NIR irradiation, the AI-MPHA NCs achieved osteosarcoma ablation by a synergistic combination of photothermal therapy and NO-gas therapy. Additionally, the cell viability of MG-63 cells decreased to 23.6% (co-incubated with AI-MPHA NCs) under irradiation with a power density at 1.0 W cm-2 for 10 min. The study proposed a novel nano-platform for NO-enhanced photothermal therapy of osteosarcoma.

DOI: https://doi.org/10.1039/d1tb01084k
ACS Appl Mater Interfaces. 2021 Sep 24.

Engineering Paclitaxel Prodrug Nanoparticles via Redox-Activatable Linkage and Effective Carriers for Enhanced Chemotherapy.

Shaojin Lu, Rui Xia, Jian Wang, Qing Pei, Zhigang Xie, Xiabin Jing.

  The current clinical performance of chemotherapy is far from satisfactory, greatly limited by insufficient delivery efficacy and serious systemic side effects. Dimeric prodrug systems are emerging as valuable strategies for boosting the antitumor outcome. Here, dimeric paclitaxel prodrugs were synthesized with different bridged linkers, and the formed prodrug nanoparticles possessed excellent colloidal stability and ultrahigh drug content. The diselenide bond containing paclitaxel prodrugs could respond to a redox-heterogeneous intracellular microenvironment for on-demand drug release and subsequently show a selective cytotoxicity toward tumor cells against normal cells. Furthermore, the optimal carrier materials were screened out according to their contribution on stability, endocytosis, cytotoxicity, biodistribution, and antitumor efficacy. Compared with DSPE-PEG, human serum albumin, and Fe-tannic acid-based complex, F127 anchored dimeric paclitaxel nanoformulations exhibited preferential tumor accumulation and potent anticancer effect. Our present work provides deep insight into the development of advanced nanoformulations with comprehensive advantages for enhancing cancer therapy.

Keywords:  carrier materials; diselenide; paclitaxel; prodrug; redox response

DOI:  https://doi.org/10.1021/acsami.1c12353
Dalton Trans. 2021 Sep 24.

A mitochondrion-targeted BODIPY-Ir(III) conjugate as a photoinduced ROS generator for the oxidative destruction of triple-negative breast cancer cells.

Liping Qiao, Jiangping Liu, Shi Kuang, Xinxing Liao, Junfeng Kou, Liangnian Ji, Hui Chao.

Photodynamic therapy (PDT) provides an alternative option to root out localized triple-negative breast cancer (TNBC) and has been experiencing a surge of research interest over recent years. In this study, we put forward a paradigm of designing novel transition metal-based PSs with the following characteristics: favorable cell-permeability, significant light-harvesting ability and prominent ROS yield. A novel BODIPY-Ir(III) conjugate has been designed as a photoinduced ROS (1O2, ˙OH and ˙O2-) generator. BODIPY-Ir is highly photoactive in subduing cancer cells in the PDT regimen with PI values ranging from 172 to 519 and EC50 in the nanomolar regime. Among various cancerous cell lines, TNBC was especially sensitive to BODIPY-Ir-mediated PDT, with a stunning EC50 value of 4.32 nM (PI = 519) under a moderate flux of visible-light irradiation (500 nm, 10.5 mW cm-2). BODIPY-Ir mainly accumulates in mitochondria and induces cell apoptosis under irradiation. Furthermore, the nanomolar antiproliferative activity of BODIPY-Ir is retained under hypoxia (2.5% O2). This work sheds light on instilling the O2-independent type I mechanism and conferring a red-shift absorption to metal-based PSs which fundamentally facilitate the clinical translation of PSs.

DOI: https://doi.org/10.1039/d1dt01460a
J Mater Chem B. 2021 Sep 23.

A flowerlike FePt/MnO2/GOx-based cascade nanoreactor with sustainable O2 supply for synergistic starvation-chemodynamic anticancer therapy.

Yunkai Kou, Zhichao Dai, Ping Cui, Zunfu Hu, Lu Tian, Feifei Zhang, Haiqiang Duan, Qiying Xia, Qingyun Liu, Xiuwen Zheng.

The development of versatile nanotheranostic agents has received increasing interest in cancer treatment. Herein, in this study, we rationally designed and prepared a novel flowerlike multifunctional cascade nanoreactor, BSA-GOx@MnO2@FePt (BGMFP), by integrating glucose oxidase (GOx), manganese dioxide (MnO2) and FePt for synergetic cancer treatment with satisfying therapeutic efficiency. In an acidic environment, intratumoral H2O2 could be decomposed to O2 to accelerate the consumption of glucose catalyzed by GOx to induce cancer starvation. Moreover, the accumulation of gluconic acid and H2O2 generated along with the consumption of glucose would in turn promote the catalytic efficiency of MnO2 and boost O2 evolution, which could enhance the efficiency of starvation therapy. Moreover, FePt as an excellent Fenton agent could simultaneously convert H2O2 to the toxic hydroxyl radical (˙OH), subsequently resulting in amplified intracellular oxidative stress and cell apoptosis. Therefore, BGMFP could catalyze a cascade of intracellular biochemical reactions and optimize the unique properties of MnO2, GOx and FePt via mutual promotion of each other to realize O2 supply, chemodynamic therapy (CDT) and starvation therapy. The anticancer results in vitro and in vivo demonstrated that BGMFP possessed remarkable tumor inhibition capacity through enhancing the starvation therapy and CDT. It is appreciated that BGMFP could be a promising platform for synergetic cancer treatment.

DOI: https://doi.org/10.1039/d1tb01539g
Antioxid Redox Signal. 2021 Sep 20.

THIOL-BASED ANTIOXIDANTS AND THE EPITHELIAL-MESENCHYMAL TRANSITION IN CANCER.

Fernando T Ogata, Alex Yuri Simoes Sato, Lucia Coppo, Roberto J Arai, Arnold I Stern, Hugo P Monteiro.

  SIGNIFICANCE: The epithelial-mesenchymal transition (EMT) is commonly associated with tumor metastasis. Oxidative and nitrosative stress are maintained in cancer cells and are involved in the EMT. Cancer cells are endowed with high levels of enzymatic and non-enzymatic antioxidants which counteract the effects of oxidative and nitrosative stress. Thiol-based antioxidant systems such as the Thioredoxin/Thioredoxin reductase (Trx/TrxR) and Glutathione/Glutaredoxin (GSH/Grx) are continually active in cancer cells, while the Thioredoxin-interacting protein (Txnip), the negative regulator of the Trx/TrxR system, is down regulated. Recent Advances: Trx/TrxR and GSH/Grx systems play a major role in maintaining EMT signaling and cancer cell progression.CRITICAL ISSUES: Enhanced stress conditions stimulated in cancer cells inhibit EMT signal-ing. The elevated expression levels of the Trx/TrxR and GSH/Grx systems in these cells provide the antioxidant protection necessary to guarantee the occurrence of the EMT.
FUTURE DIRECTIONS: Elevation of the intracellular ROS and NO concentrations in cancer cells has been viewed as a promising strategy for elimination of these cells. The devel-opment of inhibitors of GSH synthesis and of the Trx/TrxR system together with genet-ic-based strategies to enhance Txnip levels may provide the necessary means to achieve this goal.

Keywords:  Epithelial-mesenchymal transition; oxidative stress; nitrosative stress; Thioredoxin; Thioredoxin reductase; Thioredoxin-interacting protein; Glutaredoxin.

DOI:  https://doi.org/10.1089/ars.2021.0199
BMC Complement Med Ther. 2021 Sep 18. 21(1): 234

Potent Nrf2-inducing, antioxidant, and anti-inflammatory effects and identification of constituents validate the anti-cancer use of Uvaria chamae and Olax subscorpioidea.

Temidayo D Popoola, Stephanie T Guetchueng, Kenneth J Ritchie, Olufunsho Awodele, Nicola M Dempster, Oluyemi Akinloye, Satyajit D Sarker, Amos A Fatokun.

  BACKGROUND: Uvaria chamae (UC) and Olax subscorpioidea (OS) roots are included in traditional anti-cancer remedies and some studies have identified their chemopreventive/chemotherapeutic potential. This study aimed to identify some cellular/molecular mechanisms underlying such potential and the associated chemical constituents.METHODS: Effect on the viability of cancer cells was assessed using the Alamar Blue assay; ability to modulate oxidative stress was assessed using the 2',7'-dichlorofluorescein diacetate (DCFDA) assay; potential to modulate Nuclear factor erythroid 2-related factor like-2 (Nrf2) activity was assessed in the AREc32 luciferase reporter cell line; and anti-inflammatory effect was assessed using lipopolysaccharide-induced nitric oxide release model in the RAW264.7 cells (Griess Assay). Chemical constituents were identified through liquid chromatography-mass spectrometry (LC-MS).
RESULTS: Extracts up to 100 μg/ml were non-toxic or mildly toxic to HeLa, AREc32, PC3 and A549 cells (IC50 > 200 μg/ml). Each extract reduced basal and peroxide-induced levels of reactive oxygen species (ROS) in HeLa cells. OS and UC activated Nrf2, with UC producing nearly four-fold induction. Both extracts demonstrated anti-inflammatory effects. Chamanetin, isochamanetin, isouvaretin, uvaricin I and other compounds were found in U. chamae root extract.
CONCLUSION: As Nrf-2 induction, antioxidant and anti-inflammatory activities are closely linked with chemoprevention and chemotherapy of cancers, the roles of these plants in traditional anti-cancer remedies are further highlighted, as is their potential as sources of drug leads.

Keywords:  Anti-inflammatory; Antioxidant; Olax subscorpioidea; Uvaria chamae; cancer

DOI:  https://doi.org/10.1186/s12906-021-03404-0
Sci Adv. 2021 Sep 24. 7(39): eabj8833

A nonferrous ferroptosis-like strategy for antioxidant inhibition-synergized nanocatalytic tumor therapeutics.

Chenyao Wu, Zhonglong Liu, Zhixin Chen, Deliang Xu, Lisong Chen, Han Lin, Jianlin Shi.

[Figure: see text].

DOI: https://doi.org/10.1126/sciadv.abj8833
J Biomed Nanotechnol. 2021 Aug 01. 17(8): 1510-1524

Fenton Reaction Induced by Fe-Based Nanoparticles for Tumor Therapy.

Jian Zhou, Miao Lei, Xue-Liang Peng, Dai-Xu Wei, Lu-Ke Yan.

Fenton reaction, a typical inorganic reaction, is broadly utilized in the field of wastewater treatment. Recently In case of its ability to inhibit the growth of cancer cells, it has been frequently reported in cancer treatment. Using the unique tumor microenvironment in cancer cells, many iron-based nanoparticles have been developed to release iron ions in cancer cells to induce Fenton reaction. In this mini review, we outline several different types of iron-based nanoparticles and several main means to enhance Fenton reaction in cancer cells. Finally, we discussed the advantages and disadvantages of iron-based nanoparticles for cancer therapy, prospected the future development of iron-based nanoparticles. It is believed that iron-based nanoparticles can make certain contribution to the cause of human cancer in the future.

DOI: https://doi.org/10.1166/jbn.2021.3130