bims-rehoca Biomed News
on Redox homeostasis in cancer
Issue of 2021‒07‒25
thirty-one papers selected by
Vittoria Raimondi
Veneto Institute of Oncology

  1. Cancer Sci. 2021 Jul 19.
      Reactive oxygen species (ROS), a class of highly bioactive molecules, have been widely studied in various types of cancers. ROS are considered to be normal byproducts of numerous cellular processes. Typically, cancer cells exhibit higher basal levels of ROS compared to normal cells as a result of an imbalance between oxidants and antioxidants. ROS have a dual role in cell metabolism: At low to moderate levels, ROS act as signal transducers to activate cell proliferation, migration, invasion and angiogenesis. In contrast, high levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death. Extensive studies have revealed that anticancer therapies that manipulate ROS levels, including immunotherapies, show promising in vitro as well as in vivo results. In this review, we summarize molecular mechanisms and oncogenic functions that modulate ROS levels and are useful for the development of cancer therapeutic strategies. This review also provides insights into the future development of effective agents that regulate the redox system for cancer treatment.
    Keywords:  Cell Death; Neoplasms; Oxidative Stress; Reactive Oxygen Species; Therapeutics
  2. Adv Mater. 2021 Jul 23. e2101467
      The development and optimization of sonosensitizers for elevating intratumoral reactive oxygen species (ROS) are definitely appealing in current sonodynamic therapy (SDT). Given this, branched vanadium tetrasulfide (VS4 ) nanodendrites with a narrower bandgap (compared with the most extensively explored sonosensitizers) are presented as a new source of sonosensitizer, which allows a more effortless separation of sono-triggered electron-hole pairs for ROS generation. Specifically, platinum (Pt) nanoparticles and endogenous high levels of glutathione (GSH) are rationally engineered to further optimize its sono-sensitized performance. As cocatalyst, Pt is conducive to trapping electrons, whereas GSH, as a natural hole-scavenger, tends to capture holes. Compared with the pristine VS4 sonosensitizer, the GSH-Pt-VS4 nanocomposite can greatly prolong the lifetime of the charge and confer a highly efficacious ROS production activity. Furthermore, such nanoplatforms are capable of reshaping tumor microenvironments to realize ROS overproduction, contributed by overcoming tumor hypoxia to improve SDT-triggered singlet oxygen production, catalyzing endogenic hydrogen peroxide into destructive hydroxyl radicals for chemodynamic therapy, and depleting GSH to amplify intratumoral oxidative stress. All these combined effects result in a significantly efficient tumor suppression outcome. This study enriches sonosensitizer research and proves that sonosensitizers can be rationally optimized by charge separation engineering strategy.
    Keywords:  cocatalysts; hole-scavengers; sonodynamic therapy; sonosensitizers; vanadium tetrasulfide
  3. Sci Rep. 2021 Jul 21. 11(1): 14869
      Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a potential redox agent in cells. The present study investigated changes in cellular reactive oxygen species (ROS) and glutathione (GSH) levels and in antioxidant enzymes, in Tempol-treated Calu-6 and A549 lung cancer cells, normal lung WI-38 VA-13 cells, and primary pulmonary fibroblasts. Results demonstrated that Tempol (0.5-4 mM) either increased or decreased general ROS levels in lung cancer and normal cells at 48 h and specifically increased O2•- levels in these cells. In addition, Tempol differentially altered the expression and activity of antioxidant enzymes such as superoxide dismutase, catalase, and thioredoxin reductase1 (TrxR1) in A549, Calu-6, and WI-38 VA-13 cells. In particular, Tempol treatment increased TrxR1 protein levels in these cells. Tempol at 1 mM inhibited the growth of lung cancer and normal cells by about 50% at 48 h but also significantly induced cell death, as evidenced by annexin V-positive cells. Furthermore, down-regulation of TrxR1 by siRNA had some effect on ROS levels as well as cell growth inhibition and death in Tempol-treated or -untreated lung cells. In addition, some doses of Tempol significantly increased the numbers of GSH-depleted cells in both cancer cells and normal cells at 48 h. In conclusion, Tempol differentially increased or decreased levels of ROS and various antioxidant enzymes in lung cancer and normal cells, and induced growth inhibition and death in all lung cells along with an increase in O2•- levels and GSH depletion.
  4. Arch Pharm Res. 2021 Jul 24.
      In this study, we investigated the anti-cancer effects of ginsenoside Rg2 (G-Rg2) and its underlying signaling pathways in breast cancer (BC) cells. G-Rg2 significantly induced cytotoxicity and reactive oxygen species (ROS) production in MCF-7 cells among various types of BC cells including HCC1428, T47D, and BT-549. G-Rg2 significantly inhibited protein and mRNA expression of cell cycle G1-S phase regulators, including p-Rb, cyclin D1, CDK4, and CDK6, whereas it enhanced the protein and mRNA expression of cell cycle arrest and apoptotic molecules including cleaved PARP, p21, p27, p53 and Bak through ROS production. These effects were abrogated by the antioxidant N-acetyl-I-cysteine, or NADPH oxidase inhibitors, such as diphenyleneiodonium chloride and apocynin. Interestingly, G-Rg2 induced mitochondrial damage by reducing the membrane potential. G-Rg2 further activated the ROS-sensor protein, AMPK and downstream targets of AMPK activation, including PGC-1α, FOXO1, and IDH2, and downregulated mTOR activation and antioxidant response element-driven luciferase activity. Together, our data demonstrate that G-Rg2 mediates anti-cancer effects by activating cell cycle arrest and signaling pathways related to mitochondrial damage-induced ROS production and apoptosis.
    Keywords:  AMPK; Breast cancer; Cell cycle; Ginsenoside-Rg2; Mitochondrial membrane potential; Reactive oxygen species
  5. Int J Mol Sci. 2021 Jul 07. pii: 7306. [Epub ahead of print]22(14):
      In photodynamic therapy (PDT) for neoplasms, photosensitizers selectively accumulate in cancer tissue. Upon excitation with light of an optimal wavelength, the photosensitizer and surrounding molecules generate reactive oxygen species, resulting in cancer cell-specific cytotoxicity. Porphylipoprotein (PLP) has a porphyrin-based nanostructure. The porphyrin moiety of PLP is quenched because of its structure. When PLP is disrupted, the stacked porphyrins are separated into single molecules and act as photosensitizers. Unless PLP is disrupted, there is no photosensitive disorder in normal tissues. PLP can attenuate the photosensitive disorder compared with other photosensitizers and is ideal for use as a photosensitizer. However, the efficacy of PLP has not yet been evaluated. In this study, the mechanism of cancer cell-specific accumulation of PLP and its cytotoxic effect on cholangiocarcinoma cells were evaluated. The effects were investigated on normal and cancer-like mutant cells. The cytotoxicity effect of PLP PDT in cancer cells was significantly stronger than in normal cells. In addition, reactive oxygen species regulated intracellular PLP accumulation. The cytotoxic effects were also investigated using a cholangiocarcinoma cell line. The cytotoxicity of PLP PDT was significantly higher than that of laserphyrin-based PDT, a conventional type of PDT. PLP PDT could also inhibit tumor growth in vivo.
    Keywords:  cholangiocarcinoma; photodynamic therapy; porphylipoproteins; reactive oxygen species
  6. Biomaterials. 2021 Jul 10. pii: S0142-9612(21)00379-3. [Epub ahead of print]276 121023
      Nanomaterials with shifting or mixed redox states is one of the most common studied nanozyme with peroxidase-like activity for chemodynamic therapy (CDT), which can decompose hydrogen peroxide (H2O2) of tumor microenvironment into highly toxic reactive oxygen species (ROS) by a nano-catalytic way. However, most of them exhibit an insufficient catalytic efficiency due to their dependence on catalytic condition. Herein, a potential methodology is proposed to enhance their enzymatic activity by accelerating the redox cycling of these nanomaterials with shifting or mixed redox states in the presence of X-ray. In this study, the nanocomposite consisting of SnS2 nanoplates and Fe3O4 quantum dots with shifting or mixed redox states (Fe2+/Fe3+) is used to explore the strategy. Under external X-ray irradiation, SnS2 cofactor as electron donor can be triggered to transfer electrons to Fe3O4, which promotes the regeneration of Fe2+ sites on the surface of the Fe3O4. Consequently, the regenerated Fe2+ sites react with the overexpressed H2O2 to persistently generate ROS for enhanced tumor therapy. The designed nanocomposite displays the synergistic effects of radiotherapy and CDT. The strategy provides a new avenue for the development of artificial nanozymes with shifting or mixed redox states in precise cancer treatments based on X-ray-enhanced enzymatic efficacy.
    Keywords:  Nanomaterials; Nanozyme; Radiotherapy; Reactive oxygen species; Therapy
  7. J Inorg Biochem. 2021 Jul 09. pii: S0162-0134(21)00184-7. [Epub ahead of print]223 111537
      Cell death is essential for cancer, which can be induced through multiple mechanisms. Ferroptosis, a newly emerging form of non-apoptotic cell death, involves the generation of iron-dependent reactive oxygen species (ROS). In this study, we designed and synthesized two artesunate (ART) conjugated phosphorescent rhenium(I) complexes (Re(I)-ART conjugates), [Re(N^N)(CO)3(PyCH2OART)](PF6) (Re-ART-1 and Re-ART-2) (Py = pyridine, N^N = 1,10-phenanthroline (phen, in Re-ART-1) and 4,7-diphenyl-1,10-phenanthroline (DIP, in Re-ART-2)) that can specifically locate in the mitochondria of human cervical carcinoma (HeLa). Mechanism studies show that Re-ART-1 and Re-ART-2 exhibit high cytotoxicity against cancer cells lines and can induce both apoptosis and ferroptosis in HeLa cells through mitochondrial damage, caspase cascade, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation and lipid peroxidation accumulation. As a result, this work presents the rational design of Re(I)-ART conjugates as a promising strategy to induce both apoptosis and ferroptosis and improve therapeutic efficiency of cancer treatment.
    Keywords:  Anticancer activity; Apoptosis; Artesunate; Ferroptosis; Mitochondria; Rhenium(I) complex
  8. Genes Genomics. 2021 Jul 24.
      BACKGROUND: Lactucin, a naturally occurring active sesquiterpene lactone, is abundantly found in chicory and romaine lettuce. A recent study reported that lactucin could induce apoptosis in leukemia cells. However, its cytotoxicity and potential molecular mechanisms underlying cancer cell death remain unclear.OBJECTIVE: Therefore, in this study, we aimed to investigate the direct effect and underlying mechanism of action of lactucin on renal cancer cells.
    METHODS: MTT assay and flow cytometry were performed to evaluate the rate of cell proliferation and apoptosis, respectively. Western blotting, reverse transcription polymerase chain reaction, and protein stability analyses were performed to analyze the effect of lactucin on the expression of apoptosis-related proteins such as B-cell lymphoma 2 (BCL-2) and CFLAR (CASP8 and FADD like apoptosis regulator) long isoform (CFLARL) in Caki-1 human renal cancer cells. In addition, reactive oxygen species (ROS) generation was evaluated using flow cytometry.
    RESULTS: Lactucin treatment induced apoptosis in Caki-1 cells in a dose-dependent manner via activation of the caspase pathway. It downregulated BCL-2 and CFLARL expression levels by suppressing BCL-2 transcription and CFLARL protein stability, respectively. Pretreatment with N-acetyl-1-cysteine, a ROS scavenger, attenuated the lactucin-induced apoptosis and restored the BCL-2 and CFLARL expression to basal levels. Lactucin-facilitated BCL-2 downregulation was regulated at the transcriptional level through the inactivation of the NF-κB pathway.
    CONCLUSIONS: Our study is the first to demonstrate that lactucin-induced apoptosis is mediated by ROS production, which in turn activates the caspase-dependent apoptotic pathway by inhibiting BCL-2 and CFLARL expression in Caki-1 cells.
    Keywords:  Apoptosis; BCL-2; CFLARL; Lactucin; ROS; Renal cancer
  9. Ther Adv Med Oncol. 2021 ;13 17588359211027836
      Background: Trastuzumab (Herceptin) is the key systemic therapy for HER2-positive breast cancer. However, the initial response rate is limited to approximately 50% in patients. Moreover, most patients, especially at an advanced stage, eventually develop acquired resistance. Understanding the mechanisms of trastuzumab resistance is crucial for achieving better treatment outcome in this group of patients.Methods: A trastuzumab-resistant (TR) cell line was developed using the BT474 HER2-positive breast cancer cell line. Whole-transcriptome expression array was performed and the TR-related gene NDUFA4L2 was identified by differential expression analysis between BT474 and BT474-TR. Mitochondrial localization of NDUFA4L2 was confirmed by immunofluorescence and western blotting using mitochondrial fractionation. Mitochondrial function and energy metabolism were evaluated using Seahorse, ATP production, and lactate production assays, and cellular reactive oxygen species (ROS) levels were determined using DCFDA. NDUFA4L2 expression in patients was evaluated by immunohistochemistry, and relapse-free survival was analyzed using the Kaplan-Meier method.
    Results: NDUFA4L2 was highly expressed in the TR HER2-positive breast cancer cell line. High expression level of NDUFA4L2 was associated with shorter relapse-free intervals in trastuzumab-treated HER2-positive breast cancer patients. Overexpression of NDUFA4L2 enhanced Warburg effects, enhanced aerobic glycolysis, reduced oxygen consumption, and lowered ROS production. Mechanistically, overexpression of NDUFA4L2 facilitated mitochondrial relocalization of HER2 and suppressed ROS production, thus rendering cancer cells more resistant to trastuzumab treatment.
    Conclusions: We identified NDUFA4L2 as a new biomarker and potential therapeutic target for TR HER2-positive breast cancer.
    Keywords:  NDUFA4L2; Warburg effects; breast cancer; mitochondrial metabolism; trastuzumab resistance
  10. Biomaterials. 2021 Jul 08. pii: S0142-9612(21)00372-0. [Epub ahead of print]276 121016
      The microwave dynamic therapy (MDT) mediated by cytotoxic reactive oxygen species (ROS) is a promising anticancer therapeutic method. However, the therapeutic efficiency of MDT is restricted by several limitations including insufficient ROS generation, strong proangiogenic response, and low tumor-targeting efficiency. Herein, we find that Cu-based nanoparticles can produce oxygen under microwave (MW) irradiation to raise the generation of ROS, such as •O2, •OH and 1O2, especially •O2. On this basis, a nanoengineered biomimetic strategy is designed to improve the efficiency of MDT. After intravenous administration, the nanoparticles accumulate to the tumor site through targeting effect mediated by biomimetic modification, and it can continuously produce oxygen to raise the levels of ROS in tumor microenvironment under MW irradiation for MDT. Additionally, Apatinib is incorporated as antiangiogenic drug to downregulate the expression of vascular endothelial growth factor (VEGF), which can effectively inhibit the tumor angiogenesis after MDT. Hence, the tumor inhibition rate is as high as 96.79%. This study provides emerging strategies to develop multifunctional nanosystems for efficient tumor therapy by MDT.
    Keywords:  Antiangiogenesis; Biomimetic; Cu-based nanoparticles; Microwave dynamic therapy (MDT); Reactive oxygen species (ROS)
  11. Front Oncol. 2021 ;11 708263
      COVID-19 and lung cancer are two severe pulmonary diseases that cause millions of deaths globally each year. Understanding the dysregulated signaling pathways between them can benefit treating the related patients. Recent studies suggest the critical role of reactive oxygen species (ROS) in both diseases, indicating an interplay between them. Here we reviewed references showing that ROS and ROS-associated signaling pathways, specifically via NRF2, HIF-1, and Nf-κB pathways, may bridge mutual impact between COVID-19 and lung cancer. As expected, typical ROS-associated inflammation pathways (HIF-1 and Nf-κB) are activated in both diseases. The activation of both pathways in immune cells leads to an overloading immune response and exacerbates inflammation in COVID-19. In lung cancer, HIF-1 activation facilitates immune escape, while Nf-κB activation in T cells suppresses tumor growth. However, the altered NRF2 pathway show opposite trends between them, NRF2 pathways exert immunosuppressive effects in both diseases, as it represses the immune response in COVID-19 patients while facilitates the immune escape of tumor cells. Furthermore, we summarized the therapeutic targets (e.g., phytochemicals) on these ROS pathways. In sum, our review focus on the understanding of ROS Signaling in COVID-19 and lung cancer, showing that modulating ROS signaling pathways may alleviate the potentially mutual impacts between COVID-19 and lung cancer patients.
    Keywords:  COVID-19; HIF-1; NRF2; Nf-κb; lung cancer; reactive oxygen species
  12. J Ethnopharmacol. 2021 Jul 16. pii: S0378-8741(21)00663-2. [Epub ahead of print]280 114434
      ETHNOPHARMACOLOGICAL RELEVANCE: Aloe vera (L.) Burm. f. is a typical traditional Chinese medicine (TCM) collected in the Pharmacopoeia of the People's Republic of China (version 2015). It has been traditionally used for the treatment of constipation, and its potential therapeutic activities have been widely evaluated, including anti-tumor, anti-inflammatory and immune regulatory effects. The wide application of Aloe vera in food and therapy has raised safety issues and there are multiple safety assessments with a diverse toxicity and adverse effects from clinics and animals.AIM OF THE STUDY: This study aimed to investigate the safety of Aloe vera barbadensis extract C (AVBEC) in rats and analyze its anticancer activity in cell lines.
    MATERIALS AND METHODS: We administrated AVBEC orally in an acute toxicity study and a 6-month chronic toxicity study to observe and confirm its safety in Sprague-Dawley (SD) rats. Additionally, we explored the cytotoxicity of AVBEC in cancer cells and non-cancer cells. We further investigated the anti-tumor activity of AVBEC, and in the meantime, probed the function of component from AVBEC.
    RESULTS: No deaths or substance-relative toxicity were observed in the acute toxicity study or the 6-month chronic toxicity study with doses of 44.8 g·kg-1 and 4.48 g·kg-1, respectively. In the chronic toxicity study, AVBEC did not cause organ toxicity, including crucial organ structure and chemical function, and peripheral and central immune system damage. Additionally, we found that AVBEC could induce cancer cell apoptosis with a relatively higher apoptotic ratio than in non-cancer cells by decreasing adenosine triphosphate (ATP) concentration and enhancing reactive oxygen species (ROS) production. We also identified components in AVBEC using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) and probed the function of malic acid. This demonstrated that under the same circumstances, malic acid induced cell necrosis in cancer cells and non-cancer cells, while AVBEC did not.
    CONCLUSIONS: These results reveal a novel mechanism of aloe gel extract in regulating cancer cell apoptosis via modulating the mitochondrial metabolism and imply a possible application of AVBEC for the treatment of malignant cancer with the safety evaluation from rats and anticancer investigation from cancer cells and non-cancer cells.
    Keywords:  Aloe vera; Apoptosis; Breast cancer; Lung cancer; Mitochondria; Safety evaluation
  13. Int J Mol Med. 2021 09;pii: 172. [Epub ahead of print]48(3):
      Endometrial cancer (EC) is widely known as an aggressive malignancy. Due to the limited therapeutic options and poor prognosis of patients with advanced‑stage EC, there is a need to identify effective alternative treatments. Chrysin is a naturally active flavonoid (5,7‑dihydroxyflavone), which has been demonstrated to exert anticancer effects and may present a novel strategy for EC treatment. However, the role of chrysin in EC remains largely unclear. The aim of the present study was to examine the anticancer effects of chrysin on EC. The results revealed that, in addition to apoptosis, chrysin increased the LC3II expression levels and markedly accelerated the autophagic flux, suggesting that chrysin induced both the autophagy and apoptosis of EC cells. Furthermore, the inhibition of autophagy by chloroquine enhanced the inhibitory effect on cell proliferation and the promotion of the chrysin‑induced apoptosis of EC cells, indicating that chrysin‑induced autophagy was a cytoprotective mechanism. Additionally, chrysin led to the production of intracellular reactive oxygen species (ROS). N‑acetylcysteine (NAC) pretreatment significantly inhibited chrysin‑induced autophagy, suggesting that ROS activated autophagy induced by chrysin in EC cells. Furthermore, the phosphorylated (p‑)Akt and p‑mTOR levels were significantly decreased in a concentration‑dependent manner following treatment with chrysin, while NAC blocked these effects. Taken together, these findings demonstrated that chrysin‑induced autophagy via the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in EC cells.
    Keywords:  Akt/mTOR; apoptosis; autophagy; chrysin; endometrial cancer; reactive oxygen species
  14. Int J Mol Sci. 2021 Jul 16. pii: 7631. [Epub ahead of print]22(14):
      Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.
    Keywords:  DNA damage; cancer cells; cytotoxicity; glutathione peroxidase; pentathiepin; reactive oxygen species; sulfur
  15. Blood. 2021 Jul 22. 138(3): 234-245
      Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
  16. Oxid Med Cell Longev. 2021 ;2021 5522054
      Various research works have piled up conflicting evidence questioning the effect of oxidative stress in cancer. Reactive oxygen and nitrogen species (RONS) are the reactive radicals and nonradical derivatives of oxygen and nitrogen. RONS can act as a double-edged weapon. On the one hand, RONS can promote cancer initiation through activating certain signal transduction pathways that direct proliferation, survival, and stress resistance. On the other hand, they can mitigate cancer progression via their resultant oxidative stress that causes many cancer cells to die, as some recent studies have proposed that high RONS levels can limit the survival of cancer cells during certain phases of cancer development. Similarly, eukaryotic translation initiation factors are key players in the process of cellular transformation and tumorigenesis. Dysregulation of such translation initiation factors in the form of overexpression, downregulation, or phosphorylation is associated with cancer cell's altering capability of survival, metastasis, and angiogenesis. Nonetheless, eIFs can affect tumor age-related features. Data shows that alternating the eukaryotic translation initiation apparatus can impact many downstream cellular signaling pathways that directly affect cancer development. Hence, researchers have been conducting various experiments towards a new trajectory to find novel therapeutic molecular targets to improve the efficacy of anticancer drugs as well as reduce their side effects, with a special focus on oxidative stress and initiation of translation to harness their effect in cancer development. An increasing body of scientific evidence recently links oxidative stress and translation initiation factors to cancer-related signaling pathways. Therefore, in this review, we present and summarize the recent findings in this field linking certain signaling pathways related to tumorigeneses such as MAPK and PI3K, with either RONS or eIFs.
  17. J Am Chem Soc. 2021 Jul 22.
      Radiosensitizers are agents capable of amplifying injury to tumor tissues by enhancing DNA damage and fortifying production of radical oxygen species (ROS). The use of such radiosensitizers in the clinic, however, remains limited by an insufficient ability to differentiate between cancer and normal cells and by the presence of a reversible glutathione system that can diminish the amount of ROS generated. Here, to address these limitations, we design an H2O2-responsive prodrug which can be premixed with lauric acid (melting point ∼43 °C) and loaded around the surface of silica-coated bismuth nanoparticles (BSNPs) for cancer-specific photoradiotherapy. Particularly, silica coating confers BSNPs with improved chemical stability against both near-infrared light and X-rays. Upon photothermal heating, lauric acid is melted to trigger prodrug release, followed by its transformation into p-quinone methide via H2O2 stimulation to irreversibly alkylate glutathione. Concurrently, this heat boosts tumor oxygenation and helps relieve the hypoxic microenvironment. Following sequential irradiation by X-rays, BSNPs generate plentiful ROS, which act in combination with these events to synergistically induce cell death via DNA breakage and mitochondria-mediated apoptosis pathways, ultimately enabling effective inhibition of tumor growth in vivo with high tumor specificity and reduced side effects. Collectively, this work presents a promising approach for the improvement of other ROS-responsive proalkylating agents, while simultaneously highlighting a robust nanosystem for combining these prodrugs with photoradiosensitizers to realize precision photoradiotherapy.
  18. Front Cell Dev Biol. 2021 ;9 660005
      The development of temozolomide (TMZ) resistance in glioma leads to poor patient prognosis. Sorafenib, a novel diaryl urea compound and multikinase inhibitor, has the ability to effectively cross the blood-brain barrier. However, the effect of sorafenib on glioma cells and the molecular mechanism underlying the ability of sorafenib to enhance the antitumor effects of TMZ remain elusive. Here, we found that sorafenib could enhance the cytotoxic effects of TMZ in glioma cells in vitro and in vivo. Mechanistically, the combination of sorafenib and TMZ induced mitochondrial depolarization and apoptosis inducing factor (AIF) translocation from mitochondria to nuclei, and this process was dependent on STAT3 inhibition. Moreover, the combination of sorafenib and TMZ inhibited JAK2/STAT3 phosphorylation and STAT3 translocation to mitochondria. Inhibition of STAT3 activation promoted the autophagy-associated apoptosis induced by the combination of sorafenib and TMZ. Furthermore, the combined sorafenib and TMZ treatment induced oxidative stress while reactive oxygen species (ROS) clearance reversed the treatment-induced inhibition of JAK2/STAT3. The results indicate that sorafenib enhanced the temozolomide sensitivity of human glioma cells by inducing oxidative stress-mediated autophagy and JAK2/STAT3-AIF axis.
    Keywords:  AIF; JAK2/STAT3; TMZ; glioma cells; sorafenib
  19. J Renin Angiotensin Aldosterone Syst. 2021 ;2021 6191417
      Introduction: The roles of angiotensin II (Ang II) in the brain are still under investigation. In this study, we investigated if Ang II influences differentiation of human neuroblastoma cells with simultaneous activation of NADPH oxidase and reactive oxygen species (ROS). Moreover, we investigated the Ang II receptor type involved during differentiation.Methods: Human neuroblastoma cells (SH-SY5Y; 5 × 105 cells) were exposed to Ang II (600 nM) for 24 h. Differentiation was monitored by measuring MAP2 and NF-H levels. Cell size and ROS were analyzed by flow cytometry, and NADPH oxidase activation was assayed using apocynin (500 μM). Ang II receptors (ATR) activation was assayed using ATR blockers or Ang II metabolism inhibitors (10-7 M).
    Results: (1) Cell size decreased significantly in Ang II-treated cells; (2) MAP2 and ROS increased significantly in Ang II-treated cells with no changes in viability; (3) MAP2 and ROS decreased significantly in cells incubated with Ang II plus apocynin. (4) A significant decrease in MAP2 was observed in cells exposed to Ang II plus PD123.319 (AT2R blocker).
    Conclusion: Our findings suggest that Ang II influences differentiation of SH-SY5Y by increasing MAP2 through the AT2R. The increase in MAP2 and ROS were also mediated through NADPH oxidase with no cell death.
  20. PLoS One. 2021 ;16(7): e0255120
      The potential risks of environmental nanoparticles (NPs), in particular Polystyrene Nanoparticles (PNPs), is an emerging problem; specifically, the interaction of PNPs with intestinal cells has not been characterized so far. The mechanism by which polystyrene particles are transferred to humans has not yet been clarified, whether directly through ingestion from contaminated food. We evaluated the interaction between PNPs and colorectal adenocarcinoma cells (HCT116). Cells were exposed to different concentrations of PNPs, metabolic activity and the consequent cytotoxic potential were assessed through viability test; we evaluated the PNP genotoxic potential through the Cytokinesis-Block Micronucleus cytome (CBMN cyt) assay. Finally, we detected Reactive Oxygen Species (ROS) production after NPs exposure and performed Western Blot analysis to analyze the enzymes (SOD1, SOD2, Catalase, Glutathione Peroxidase) involved in the cell detoxification process that comes into play during the cell-PNPs interaction. This work analyzes the cyto and genotoxicity of PNPs in the colorectal HCT116 cell line, in particular the potential damage from oxidative stress produced by PNPs inside the cells related to the consequent nuclear damage. Our results show moderate toxicity of PNPs both in terms of ROS production and DNA damage. Further studies will be needed on different cell lines to have a more complete picture of the impact of environmental pollution on human health in terms of PNPs cytotoxicity and genotoxicity.
  21. Toxicol Appl Pharmacol. 2021 Jul 15. pii: S0041-008X(21)00250-7. [Epub ahead of print] 115646
      Oral Squamous Cell Carcinoma (OSCC) is the sixth most common cancer worldwide. Chemoresistance is a critical problem in OSCC leading to therapeutic failure and tumour recurrence. Recently, autophagy has acquired an emerging interest in cancer as it has been shown to be frequently activated in tumour cells treated with chemotherapeutics. Whether drug-induced autophagy represents a mechanism that allows cancer cells to survive or a pro-death mechanism associated with apoptosis remains controversial. This study evaluated the cellular response to cisplatin and the role of autophagy in mediating cisplatin resistance in OSCC cells. Our results demonstrated that cisplatin concurrently induced apoptosis and autophagy in OSCC cell lines partially through the ROS/JNK pathway. Moreover, inhibition of cisplatin-induced apoptosis abrogated autophagy, indicating a complex interplay between these pathways. Cisplatin-induced autophagy does not appear to elicit a pro-survival effect in OSCC as early-stage autophagy inhibition, using either a pharmacological inhibitor or knockdown of the key autophagy protein ATG5, did not sensitise cells to cisplatin. Additionally, autophagy did not play a role in acquired resistance to cisplatin in our novel cisplatin-resistant OSSC cell line (SCC-4cisR) obtained by pulsed stepwise exposure of SCC-4 cells to cisplatin (~14-fold change in sensitivity). There was no change in the basal levels of autophagy in the SCC-4cisR cells compared to the SCC-4 cells. Furthermore, a significant increase in cisplatin-induced autophagy was observed only in the SCC-4 cells, but not in the derived SCC-4cisR cells. Collectively, these data indicate that autophagy may not be implicated in acquired cisplatin resistance in OSCC.
    Keywords:  Apoptosis; Autophagy; Chemoresistance; Oral squamous cell carcinoma; Reactive oxygen species; c-Jun N-terminal kinase
  22. Int J Mol Sci. 2021 Jul 02. pii: 7168. [Epub ahead of print]22(13):
      Osteosarcoma is a common malignant bone tumor in clinical orthopedics. Iron chelators have inhibitory effects on many cancers, but their effects and mechanisms in osteosarcoma are still uncertain. Our in vitro results show that deferoxamine (DFO) and deferasirox (DFX), two iron chelators, significantly inhibited the proliferation of osteosarcoma cells (MG-63, MNNG/HOS and K7M2). The viability of osteosarcoma cells was decreased by DFO and DFX in a concentration-dependent manner. DFO and DFX generated reactive oxygen species (ROS), altered iron metabolism and triggered apoptosis in osteosarcoma cells. Iron chelator-induced apoptosis was due to the activation of the MAPK signaling pathway, with increased phosphorylation levels of JNK, p38 and ERK, and ROS generation; in this process, the expression of C-caspase-3 and C-PARP increased. In an orthotopic osteosarcoma transplantation model, iron chelators (20 mg/kg every day, Ip, for 14 days) significantly inhibited the growth of the tumor. Immunohistochemical analysis showed that iron metabolism was altered, apoptosis was promoted, and malignant proliferation was reduced with iron chelators in the tumor tissues. In conclusion, we observed that iron chelators induced apoptosis in osteosarcoma by activating the ROS-related MAPK signaling pathway. Because iron is crucial for cell proliferation, iron chelators may provide a novel therapeutic strategy for osteosarcoma.
    Keywords:  MAPK signaling pathway; ROS; apoptosis; iron chelators; iron metabolism; osteosarcoma
  23. Int J Oncol. 2021 Aug;pii: 63. [Epub ahead of print]59(2):
      NADPH oxidases (NOXs) are a family of transmembrane proteins that generate reactive oxygen species. It was previously reported that patients with colon cancer who had high NOX5 expression had poor prognosis. However, no studies have investigated the cellular functions of NOX5 in colon cancer. The present study aimed to clarify the relationship between NOX5 and cancer development using an in vitro model. Reverse transcription‑quantitative PCR was performed to determine the NOX5 expression levels of colon cancer cell lines. NOX5‑knockdown experiments were conducted, and the effect on cell proliferation, migration, and invasion were analyzed. In addition, mRNA microarray was conducted to assess changes in gene profile. NOX5 mRNA expression was high in HCT116 cells and moderate in SW48 cells. NOX5 knockdown significantly inhibited cell migration and invasion in both HCT116 and SW48 cells; however, NOX5 knockdown reduced cell proliferation in only HCT116 cells. mRNA microarrays revealed a strong relationship between NOX5 expression levels and integrin‑linked kinase signaling pathways. The NOX5 expression in colon cancer cells affected cancer progression, especially cell motility. NOX5 may be a novel therapeutic target for the future development of treatments for colon cancer.
    Keywords:  ILK signaling; NOX; ROS; cellular motility; colon cancer
  24. Int J Mol Sci. 2021 Jul 09. pii: 7379. [Epub ahead of print]22(14):
      The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.
    Keywords:  cisplatin resistance; metabolism; oxidative metabolism; reactive oxygen species
  25. Int J Mol Sci. 2021 Jul 13. pii: 7509. [Epub ahead of print]22(14):
      Oral cancer (OC) has been attracted research attention in recent years as result of its high morbidity and mortality. Costunolide (CTD) possesses potential anticancer and bioactive abilities that have been confirmed in several types of cancers. However, its effects on oral cancer remain unclear. This study investigated the potential anticancer ability and underlying mechanisms of CTD in OC in vivo and in vitro. Cell viability and anchorage-independent colony formation assays were performed to examine the antigrowth effects of CTD on OC cells; assessments for migration and invasion of OC cells were conducted by transwell; Cell cycle and apoptosis were investigated by flow cytometry and verified by immunoblotting. The results revealed that CTD suppressed the proliferation, migration and invasion of oral cancer cells effectively and induced cell cycle arrest and apoptosis; regarding the mechanism, CTD bound to AKT directly by binding assay and repressed AKT activities through kinase assay, which thereby downregulating the downstream of AKT. Furthermore, CTD remarkably promotes the generation of reactive oxygen species by flow cytometry assay, leading to cell apoptosis. Notably, CTD strongly suppresses cell-derived xenograft OC tumor growth in an in vivo mouse model. In conclusion, our results suggested that costunolide might prevent progression of OC and promise to be a novel AKT inhibitor.
    Keywords:  AKT pathway; ROS; apoptosis; costunolide; oral cancer
  26. Neurochem Int. 2021 Jul 19. pii: S0197-0186(21)00183-2. [Epub ahead of print]149 105137
      Glioblastoma (GB) is the most common and aggressive primary malignant astrocytoma correlated with poor patient survival. There are no curative treatments for GB, and it becomes resistant to chemotherapy, radiation therapy, and immunotherapy. Resistance in GB cells is closely related to their states of redox imbalance, and the role of reactive oxygen species and its impact on cancer cell survival is still far from elucidation. Boron-containing compounds, especially boric acid (BA) and borax (BX) exhibited interesting biological effects involving antibacterial, antiviral, anti-cancerogenic, anti-mutagenic, anti-inflammatory as well as anti-oxidative features. Recent studies indicated that certain boron compounds could be cytotoxic on human GB. Nevertheless, there is gap of knowledge in the literature on exploring the underlying mechanisms of anti-GB action by boron compounds. Here, we identified and compared the potential anti-GB effect of both BA and BX, and revealed their underlying anti-GB mechanism. We performed cell viability, oxidative alterations, oxidative DNA damage potential assays, and explored the inflammatory responses and gene expression changes by real-time PCR using U-87MG cells. We found that BA and BX led to a remarkable reduction in U-87MG cell viability in a concentration-dependent manner. We also found that boron compounds increased the total oxidative status and MDA levels along with the SOD and CAT enzyme activities and decreased total antioxidant capacity and GSH levels in U-87MG cells without inducing DNA damage. The cytokine levels of cancer cells were also altered. We verified the selectivity of the compounds using a normal cell line, HaCaT and found an exact opposite condition after treating HaCaT cells with BA and BX. BA applications were more effective than BX on U-87MG cell line in terms of increasing MDA levels, SOD and CAT enzyme activities, and decreasing Interleukin-1α, Interleukin-6 and Tumor necrosis factor- α (TNF- α) levels. We finally observed that anticancer effect of BA and BX were associated with the BRAF/MAPK, PTEN and PI3K/AKT signaling pathways in respect of downregulatory manner. Especially, BA application was found more favorable because of its inhibitory effect on PIK3CA, PIK3R1, PTEN and RAF1 genes. In conclusion, our analysis indicated that boron compounds may be safe and promising for effective treatment of GB.
    Keywords:  Anticancer; Borax; Boric acid; Boron; Cytotoxicity; Gene expression; Glioblastoma; Inflammatory response; Oxidative alteration
  27. Amino Acids. 2021 Jul 22.
      Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.
    Keywords:  Cancer; Disease; Proline; Redox
  28. Cell Death Discov. 2021 Jul 21. 7(1): 188
      Hepatocellular carcinoma (HCC) recurrence after liver transplantation remains a significant clinical problem. Ischemia-reperfusion injury (IRI) occurred inevitably at the early phase after liver transplantation (LT) spawns a significant risk of HCC recurrence. However, their linkage and IRI-derived risk factors for HCC recurrence remain exclusive. Understanding the mechanism of post-transplantation hepatic injury could provide new strategies to prevent the later event of HCC recurrence. We demonstrated that glutathione S-transferase A2 (GSTA2) expression was significantly associated with early phase hepatic and systemic injury and ROS level after liver transplantation. Early phase circulating GSTA2 (EPCGSTA2) protein was a significant predictor of HCC recurrence and survival. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. Enhancement of GSTA2 could protect HCC cells against H2O2-induced cell death by compensating for the elevated ROS stress. We also demonstrated that GSTA2 played crucial roles in regulating the ROS-associated JNK and AKT signaling pathways and ROS metabolism in HCCs in responding to a dynamic ROS environment. Functionally, endogenous or exogenous upregulation of GSTA2 could promote HCC growth and invasion through activating the epithelial-mesenchymal-transition process. Targeted inhibition of GSTA2 could suppress HCC growth and metastasis. In conclusion, GSTA2 could be a novel prognostic and therapeutic target to combat HCC recurrence after liver transplantation.
  29. Oncogene. 2021 Jul 21.
      Obesity affects more than 650 million individuals worldwide and is a well-established risk factor for the development of hepatocellular carcinoma (HCC). Oxidative stress can be considered as a bona fide tumor promoter, contributing to the initiation and progression of liver cancer. Indeed, one of the key events involved in HCC progression is excessive levels of reactive oxygen species (ROS) resulting from the fatty acid influx and chronic inflammation. This review provides insights into the different intracellular sources of obesity-induced ROS and molecular mechanisms responsible for hepatic tumorigenesis. In addition, we highlight recent findings pointing to the role of the dysregulated activity of BCL-2 proteins and protein tyrosine phosphatases (PTPs) in the generation of hepatic oxidative stress and ROS-mediated dysfunctional signaling, respectively. Finally, we discuss the potential and challenges of novel nanotechnology strategies to prevent ROS formation in obesity-associated HCC.
  30. Neurochem Int. 2021 Jul 16. pii: S0197-0186(21)00182-0. [Epub ahead of print]149 105136
      Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.
    Keywords:  Antioxidant; Glioblastoma; ROS; Temozolomide
  31. Cancers (Basel). 2021 Jul 15. pii: 3548. [Epub ahead of print]13(14):
      The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol's nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol's effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol's action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.
    Keywords:  DNA adducts; acetaldehyde; alcohol use disorders (AUD); cancer; cancer stem cells (CSC); epigenetic changes; ethanol oxidative and nonoxidative metabolism; protein damage; reactive oxygen species (ROS)