bims-rehoca 2021-11-28 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–11–28
thirty-six papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression.
Hemin enhances radiosensitivity of lung cancer cells through ferroptosis.
Shikonin Induced Program Cell Death through Generation of Reactive Oxygen Species in Renal Cancer Cells.
Redox regulation of DUBs and its therapeutic implications in cancer.
Blockade of Cellular Energy Metabolism through 6-Aminonicotinamide Reduces Proliferation of Non-Small Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress.
One-Pot Synthesis of Multifunctional Carbon-Based Nanoparticle-supported Dispersed Cu2+ Disrupts Redox Homeostasis to Enhance CDT.
JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4-PERK-CHOP Axis in Ovarian Cancer Cells.
Regulation of ROS-Dependent JNK Pathway by 2'-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells.
Evodiamine induces ROS-Dependent cytotoxicity in human gastric cancer cells via TRPV1/Ca2+ pathway.
Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma.
Bufalin Induces Programmed Necroptosis in Triple-Negative Breast Cancer Drug-Resistant Cell Lines through RIP1/ROS-Mediated Pathway.
AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells.
Peroxiporins Are Induced upon Oxidative Stress Insult and Are Associated with Oxidative Stress Resistance in Colon Cancer Cell Lines.
Cannabidiol Induces Cell Death in Human Lung Cancer Cells and Cancer Stem Cells.
β-sitosterol induces reactive oxygen species-mediated apoptosis in human hepatocellular carcinoma cell line.
Distinct mechanism of action for antitumoral neutral cyclometalated Pt(II)-complexes bearing antifungal imidazolyl-based drugs.
The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism.
Tumour Microenvironment Stress Promotes the Development of Drug Resistance.
FOXM1-mediated activation of phospholipase D1 promotes lipid droplet accumulation and reduces ROS to support paclitaxel resistance in metastatic cancer cells.
Effects of Iodonium Analogs on Nadph Oxidase 1 in Human Colon Cancer Cells.
The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells.
An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival.
Oxidative Stress and Autophagy as Key Targets in Melanoma Cell Fate.
The double faced role of xanthine oxidoreductase in cancer.
Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells.
The TRPA1 Channel Amplifies the Oxidative Stress Signal in Melanoma.
A Derivative of Piperlongumine and Ligustrazine as a Potential Thioredoxin Reductase Inhibitor in Drug-Resistant Hepatocellular Carcinoma.
Antineoplastic effectiveness of silver nanoparticles synthesized from Onopordum acanthium L. extract (AgNPs-OAL) toward MDA-MB231 breast cancer cells.
Selective cytotoxicity mechanisms and biodistribution of diamond nanoparticles on the skin cancer in C57 mouse.
Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.
Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy.
Pulmonary Delivery of Reactive Oxygen Species/Glutathione-Responsive Paclitaxel Dimeric Nanoparticles Improved Therapeutic Indices against Metastatic Lung Cancer.
Internalized Nanoceria Modify the Radiation-Sensitivity Profile of MDA MB231 Breast Carcinoma Cells.
The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90.
The Preliminary Study on the Proapoptotic Effect of Reduced Graphene Oxide in Breast Cancer Cell Lines.
Deep-Tissue Fluorescence Imaging Study of Reactive Oxygen Species in a Tumor Microenvironment.

Antioxidants (Basel). 2021 Nov 19. pii: 1838. [Epub ahead of print]10(11):

Mitochondrial Redox Metabolism: The Epicenter of Metabolism during Cancer Progression.

Feroza K Choudhury.

  Mitochondrial redox metabolism is the central component in the cellular metabolic landscape, where anabolic and catabolic pathways are reprogrammed to maintain optimum redox homeostasis. During different stages of cancer, the mitochondrial redox status plays an active role in navigating cancer cells' progression and regulating metabolic adaptation according to the constraints of each stage. Mitochondrial reactive oxygen species (ROS) accumulation induces malignant transformation. Once vigorous cell proliferation renders the core of the solid tumor hypoxic, the mitochondrial electron transport chain mediates ROS signaling for bringing about cellular adaptation to hypoxia. Highly aggressive cells are selected in this process, which are capable of progressing through the enhanced oxidative stress encountered during different stages of metastasis for distant colonization. Mitochondrial oxidative metabolism is suppressed to lower ROS generation, and the overall cellular metabolism is reprogrammed to maintain the optimum NADPH level in the mitochondria required for redox homeostasis. After reaching the distant organ, the intrinsic metabolic limitations of that organ dictate the success of colonization and flexibility of the mitochondrial metabolism of cancer cells plays a pivotal role in their adaptation to the new environment.

Keywords:  ROS signaling; distant colonization; metastasis; mitochondrial redox metabolism; tumor development

DOI:  https://doi.org/10.3390/antiox10111838
Exp Cell Res. 2021 Nov 23. pii: S0014-4827(21)00502-4. [Epub ahead of print] 112946

Hemin enhances radiosensitivity of lung cancer cells through ferroptosis.

Waleed Abdelbagi Almahi, K N Yu, Fathelrahman Mohammed, Peizhong Kong, Wei Han.

  The principle underlying radiotherapy is to kill cancer cells while minimizing the harmful effects on non-cancer cells, which has still remained as a major challenge. In relation, ferroptosis has recently been proposed as a novel mechanism of radiation-induced cell death. In this study, we investigated and demonstrated the role of Hemin as an iron overloading agent in the generation of reactive oxygen species (ROS) induced by ionizing radiation in lung cancer and non-cancer cells. It was found that the presence of Hemin in irradiated lung cancer cells enhanced the productivity of initial ROS, resulting in lipid peroxidation and subsequent ferroptosis. We observed that application of Hemin as a co-treatment increased the activity of GPx4 degradation in both cancer and normal lung cells. Furthermore, Hemin protected normal lung cells against radiation-induced cell death, in that it suppressed ROS after radiation, and boosted the production of bilirubin which was a lipophilic ROS antioxidant. In addition, we demonstrated significant FTH1 expression in normal lung cells when compared to lung cancer cells, which prevented iron from playing a role in increasing IR-induced cell death. Our findings demonstrated that Hemin had a dual function in enhancing the radiosensitivity of ferroptosis in lung cancer cells while promoting cell survival in normal lung cells.

Keywords:  Bilirubin; FTH1; Ferroptosis; GPx4; Hemin; ROS; Radiosensitivity

DOI:  https://doi.org/10.1016/j.yexcr.2021.112946
Antioxidants (Basel). 2021 Nov 18. pii: 1831. [Epub ahead of print]10(11):

Shikonin Induced Program Cell Death through Generation of Reactive Oxygen Species in Renal Cancer Cells.

Ming-Feng Tsai, Shih-Ming Chen, Ann-Zhi Ong, Yi-Hsuan Chung, Pei-Ni Chen, Yi-Hsien Hsieh, Yu-Ting Kang, Li-Sung Hsu.

  Shikonin mitigated tumor cell proliferation by elevating reactive oxygen species (ROS) levels. Herein, we investigated the effects of shikonin on renal cancer cell (RCC) cell proliferation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that shikonin dose-dependently reduced the proliferation of Caki-1 and ACHN cells. Shikonin remarkably triggered necrosis and apoptosis in Caki-1 and ACHN cells in proportion to its concentration. Moreover, necrostatin-1 recovered cell viability in the presence of shikonin. Elevated ROS levels and mitochondrial dysfunction were also found in shikonin treatment groups. Pretreatment with N-acetyl cysteine remarkably mitigated shikonin-induced cell death and ROS generation. Western blot analysis revealed that shikonin reduced pro-PARP, pro-caspase-3, and Bcl-2 expression and increased cleavage PARP expression. Enhanced autophagy was also found in the shikonin-treated group as evidenced by acridine orange staining. Moreover, light chain 3B (LC3B)-II accumulation and enhanced p62 expression indicated that autophagy occurred in the shikonin-treated group. LC3B knockdown considerably recovered cell viability in the presence of shikonin. Shikonin treatment elevated p38 activity in a dose-dependent manner. In conclusion, our results revealed that shikonin triggered programmed cell death via the elevation of ROS level and p38 activity in different types of RCC cells. These findings suggested that shikonin may be a potential anti-RCC agent.

Keywords:  programed cell death; reactive oxygen species; renal cell carcinoma; shikonin

DOI:  https://doi.org/10.3390/antiox10111831
Redox Biol. 2021 Nov 20. pii: S2213-2317(21)00354-2. [Epub ahead of print]48 102194

Redox regulation of DUBs and its therapeutic implications in cancer.

Apoorvi Tyagi, Saba Haq, Suresh Ramakrishna.

  Reactive oxygen species (ROS) act as a double-edged sword in cancer, where low levels of ROS are beneficial but excessive accumulation leads to cancer progression. Elevated levels of ROS in cancer are counteracted by the antioxidant defense system. An imbalance between ROS generation and the antioxidant system alters gene expression and cellular signaling, leading to cancer progression or death. Post-translational modifications, such as ubiquitination, phosphorylation, and SUMOylation, play a critical role in the maintenance of ROS homeostasis by controlling ROS production and clearance. Recent evidence suggests that deubiquitinating enzymes (DUBs)-mediated ubiquitin removal from substrates is regulated by ROS. ROS-mediated oxidation of the catalytic cysteine (Cys) of DUBs, leading to their reversible inactivation, has emerged as a key mechanism regulating DUB-controlled cellular events. A better understanding of the mechanism by which DUBs are susceptible to ROS and exploring the ways to utilize ROS to pharmacologically modulate DUB-mediated signaling pathways might provide new insight for anticancer therapeutics. This review assesses the recent findings regarding ROS-mediated signaling in cancers, emphasizes DUB regulation by oxidation, highlights the relevant recent findings, and proposes directions of future research based on the ROS-induced modifications of DUB activity.

Keywords:  Anticancer drugs; Antioxidants; Superoxide; Therapeutics; Ubiquitin proteasome system

DOI:  https://doi.org/10.1016/j.redox.2021.102194
Biology (Basel). 2021 Oct 22. pii: 1088. [Epub ahead of print]10(11):

Blockade of Cellular Energy Metabolism through 6-Aminonicotinamide Reduces Proliferation of Non-Small Lung Cancer Cells by Inducing Endoplasmic Reticulum Stress.

Neha Kaushik, Nagendra Kumar Kaushik, Eun Ha Choi, June Hyun Kim.

  The pentose phosphate pathway (PPP) is the most common pathway in most cancer cells and stimulates antioxidant defense mechanisms and synthesis of biomolecule precursors. It is believed that cancer cells persistently ameliorate glucose flux into the PPP to maintain their anabolic requirements and adjust oxidative stress. TCGA analyses have indicated the upregulation of enzymes involved in PPP in lung cancer. Hence, the present study aimed to determine whether the pharmacological blockade of glucose 6-phosphate dehydrogenase (G6PD), the primary and rate-limiting enzyme involved in PPP, using 6-aminonicotinamide (6-AN), could induce antiproliferative activity in two lung cancer cell lines. Exposure to 6-AN suppressed lactate production and glucose consumption, modified the mitochondrial potential and redox balance, and thereby induced the endoplasmic reticulum (ER) stress to reduce lung cancer cell proliferation and govern cellular apoptosis. Collectively, this is the first study in which PPP blockade by 6-AN causes reactive oxygen species (ROS)-mediated apoptosis by ER stress in lung cancer cells. Further preclinical studies will be conducted to validate the biological applicability of these findings.

Keywords:  endoplasmic reticulum stress; lung cancer; metabolic inhibitor; mitochondrial activity

DOI:  https://doi.org/10.3390/biology10111088
Angew Chem Int Ed Engl. 2021 Nov 23.

One-Pot Synthesis of Multifunctional Carbon-Based Nanoparticle-supported Dispersed Cu2+ Disrupts Redox Homeostasis to Enhance CDT.

Jun Lu, Zhongyao Jiang, Jie Ren, Wei Zhang, Ping Li, Zhenzhen Chen, Wen Zhang, Hui Wang, Bo Tang.

  In chemodynamic therapy (CDT), the levels of reactive oxygen species (ROS) production plays an important role for evaluating the therapeutic efficacy. However, the high levels of glutathione (GSH) in tumor cells consume the ROS, directly reducing the therapeutic efficiency. Herein, we synthesized carbon-based nanoparticle (Cu-cys CBNPs) using one-pot strategy, which consume GSH via redox reactions to produce Cu+ that catalyze H2O2 to produce ·OH, thus the ROS level was observably increased through this synergistic effect. In vivo experiments further revealed that Cu-cys CBNPs could effectively inhibit tumor growth. Additionally, Cu-cys CBNPs can affect the activity of some protein sulfhydryl groups in cells, which was assessed by rdTOP-ABPP assay. In general, this study not only provides a potential CDT drug, but also provides a strategy for one-pot synthesis of multifunctional nanomaterials.

Keywords:  anti-tumor drug; chemodynamic therapy; multifunctional nanoplatforms; one-pot method

DOI:  https://doi.org/10.1002/anie.202114373
Int J Mol Sci. 2021 Nov 12. pii: 12264. [Epub ahead of print]22(22):

JI017, a Complex Herbal Medication, Induces Apoptosis via the Nox4-PERK-CHOP Axis in Ovarian Cancer Cells.

Taewoo Kim, Seong-Gyu Ko.

  Many anti-cancer drugs, including paclitaxel and etoposide, have originated and been developed from natural products, and traditional herbal medicines have fewer adverse effects and lesser toxicity than anti-tumor reagents. Therefore, we developed a novel complex herbal medicine, JI017, which mediates endoplasmic reticulum (ER) stress and apoptosis through the Nox4-PERK-CHOP signaling pathway in ovarian cancer cells. JI017 treatment increases the expression of GRP78, ATF4, and CHOP and the phosphorylation of PERK and eIF2α via the upregulation of Nox4. Furthermore, it increases the release of intracellular reactive oxygen species (ROS), the production of intracellular Ca2+, and the activation of exosomal GRP78 and cell lysate GRP78. Combination treatment using the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (TG) and JI017 reportedly induces increased ER stress and cell death in comparison to the control; however, knockdown experiments of PERK and CHOP indicated suppressed apoptosis and ER stress in JI017-treated ovarian cancer cells. Furthermore, targeting Nox4 using specific siRNA and pharmacological ROS inhibitors, including N-acetylcystein and diphenylene iodonium, blocked apoptosis and ER stress in JI017-treated ovarian cancer cells. In the radioresistant ovarian cancer model, when compared to JI017 alone, JI017 co-treatment with radiation induced greater cell death and resulted in overcoming radioresistance by inhibiting epithelial-mesenchymal-transition-related phenomena such as the reduction of E-cadherin and the increase of N-cadherin, vimentin, Slug, and Snail. These findings suggest that JI017 is a powerful anti-cancer drug for ovarian cancer treatment and that its combination treatment with radiation may be a novel therapeutic strategy for radioresistant ovarian cancer.

Keywords:  ER stress; JI017; Nox4; ROS; exosome

DOI:  https://doi.org/10.3390/ijms222212264
Pharmaceutics. 2021 Oct 26. pii: 1794. [Epub ahead of print]13(11):

Regulation of ROS-Dependent JNK Pathway by 2'-Hydroxycinnamaldehyde Inducing Apoptosis in Human Promyelocytic HL-60 Leukemia Cells.

Kyung-Sook Chung, Chae-Bin Yoo, Jeong-Hun Lee, Hwi-Ho Lee, Sang-Eun Park, Hee-Soo Han, Su-Yeon Lee, Byoung-Mok Kwon, Jung-Hye Choi, Kyung-Tae Lee.

  The present study demonstrated that 2'-hydroxycinnamaldehyde (2'-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expression, (3) cytochrome c release into the cytosol, (4) loss of mitochondrial membrane potential (ΔΨm), and (5) caspase activation. 2'-HCA also induced the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase1/2 (ERK1/2) in HL-60 cells. The pharmacological and genetic inhibition of JNK effectively prevented 2'-HCA-induced apoptosis and activator protein-1 (AP-1)-DNA binding. In addition, 2'-HCA resulted in the accumulation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH) and protein thiols (PSH) in HL-60 cells. NAC treatment abrogated 2'-HCA-induced JNK phosphorylation, AP-1-DNA binding, and Bim mitochondrial translocation, suggesting that oxidative stress may be required for 2'-HCA-induced intrinsic apoptosis. Xenograft mice inoculated with HL-60 leukemia cells demonstrated that the intraperitoneal administration of 2'-HCA inhibited tumor growth by increasing of TUNEL staining, the expression levels of nitrotyrosine and pro-apoptotic proteins, but reducing of PCNA protein expression. Taken together, our findings suggest that 2'-HCA induces apoptosis via the ROS-dependent JNK pathway and could be considered as a potential therapeutic agent for leukemia.

Keywords:  2′-hydroxycinnamaldehyde; Bim; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/pharmaceutics13111794
Chem Biol Interact. 2021 Nov 19. pii: S0009-2797(21)00394-X. [Epub ahead of print]351 109756

Evodiamine induces ROS-Dependent cytotoxicity in human gastric cancer cells via TRPV1/Ca2+ pathway.

Liping Liu, Xiaodong Sun, Yunliang Guo, Keli Ge.

  Evodiamine (EVO), a key active ingredient of the fruit of Evodiae fructus, is provided with antitumor effects (mainly cytotoxic effect) including proliferation inhibition, cell cycle arrest, apoptosis, and metastasis inhibition. Our study aims to explain the underlying role of TRPV1/Ca2+ in EVO-induced cytotoxicity in human gastric cancer cells. Human gastric cancer line BGC-823 was used to study EVO-induced cytotoxicity. Cell viability was examined using CCK-8 assay. Apoptosis was examined using Annexin V-FITC/PI staining assay. Intracellular ROS ([ROS]i) levels were examined using DCFH-DA assay. Mitochondrial morphology was examined using Mitotracker Green staining. Mitochondrial membrane potential (Δψm) were examined using JC-1 assay. Intracellular Ca2+ levels ([Ca2+]i) were examined using Fluo-4 AM assay. Mitochondrial ROS ([ROS]m)levels were examined using Mitotracker Green/MitoSOX Red staining. Mitochondrial Ca2+ ([Ca2+]m)levels were examined using Mitotracker Green/Rhod-2 Red staining. The protein levels was detected by Western blot. EVO exposure causes significant ROS generation and apoptotic cell death. Pretreatment of EUK134 significantly ameliorated EVO-induced apoptotic cell death. Furthermore, EVO exposure induced [ROS]i generation and mitochondrial dysfunction, including [ROS]m generation and Δψm dissipation, which can be significantly attenuated by pre-incubation of rotenone indicating that [ROS]m is the main source of EVO-induced intracellular ROS generation. Importantly, EVO-induced cytotoxicity was significantly ameliorated by intracellular Ca2+ chelation, confirming that EVO induces cell death through Ca2+ overload. Pharmacological and genetic inhibition of TRPV1 could significantly attenuate Ca2+ influx, ROS generation and apoptotic cell death induced by EVO exposure, while exogenous TRPV1 overexpression could augment the EVO-induced cytotoxicity. Moreover, genetic inhibition of mitochondrial calcium uniporter (MCU) attenuated EVO-induced cell death and mitochondrial dysfunction. EVO exposure induced endoplasmic reticulum (ER) stress demonstrated by the activation of PERK/CHOP in cells exposed to EVO, and PERK/CHOP activation was depleted by EUK134 pre-treatment. Our results support the concept that EVO induces ROS-dependent cytotoxicity via TRPV1/Ca2+ Pathway.

Keywords:  Ca(2+); Cytotoxicity; Evodiamine; Human gastric cancer; Reactive oxygen species; Transient receptor potential vanilloid 1

DOI:  https://doi.org/10.1016/j.cbi.2021.109756
Cells. 2021 Oct 28. pii: 2936. [Epub ahead of print]10(11):

Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma.

Jinthe Van Loenhout, Laurie Freire Boullosa, Delphine Quatannens, Jorrit De Waele, Céline Merlin, Hilde Lambrechts, Ho Wa Lau, Christophe Hermans, Abraham Lin, Filip Lardon, Marc Peeters, Annemie Bogaerts, Evelien Smits, Christophe Deben.

  Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We investigated a novel reactive oxygen species (ROS)-inducing combination treatment strategy, by increasing exogenous ROS via cold atmospheric plasma and inhibiting the endogenous protective antioxidant system via auranofin (AF), a thioredoxin reductase 1 (TrxR) inhibitor. The sequential combination treatment of AF and cold atmospheric plasma-treated PBS (pPBS), or AF and direct plasma application, resulted in a synergistic response in 2D and 3D GBM cell cultures, respectively. Differences in the baseline protein levels related to the antioxidant systems explained the cell-line-dependent sensitivity towards the combination treatment. The highest decrease of TrxR activity and GSH levels was observed after combination treatment of AF and pPBS when compared to AF and pPBS monotherapies. This combination also led to the highest accumulation of intracellular ROS. We confirmed a ROS-mediated response to the combination of AF and pPBS, which was able to induce distinct cell death mechanisms. On the one hand, an increase in caspase-3/7 activity, with an increase in the proportion of annexin V positive cells, indicates the induction of apoptosis in the GBM cells. On the other hand, lipid peroxidation and inhibition of cell death through an iron chelator suggest the involvement of ferroptosis in the GBM cell lines. Both cell death mechanisms induced by the combination of AF and pPBS resulted in a significant increase in danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation, indicating a potential increase in immunogenicity, although the phagocytotic capacity of dendritic cells was inhibited by AF. In vivo, sequential combination treatment of AF and cold atmospheric plasma both reduced tumor growth kinetics and prolonged survival in GBM-bearing mice. Thus, our study provides a novel therapeutic strategy for GBM to enhance the efficacy of oxidative stress-inducing therapy through a combination of AF and cold atmospheric plasma.

Keywords:  auranofin; cancer cell death; cold atmospheric plasma; glioblastoma; oxidative stress

DOI:  https://doi.org/10.3390/cells10112936
Chin J Integr Med. 2021 Nov 26.

Bufalin Induces Programmed Necroptosis in Triple-Negative Breast Cancer Drug-Resistant Cell Lines through RIP1/ROS-Mediated Pathway.

Xiao-Dan Liu, Cheng-Yang Song, Cui-Cui Kong, Xin Tian.

   OBJECTIVE: To explore the effect and mechanism of action of bufalin in triple-negative breast cancer (TNBC) drug-resistant cell lines.
METHODS: The normal human mammary epithelial cell line, TNBC cell line, TNBC adriamycin-resistant cell line, and TNBC docetaxel-resistant cell line were treated with different doses of bufalin (0-1,000 nmol/L) at different time points (0-72 h). Propidium iodide staining, AV-FITC/PI double staining, Hoechst 33342/PI double staining and transmission electron microscopy (TEM) were used to evaluate the death patterns of the cell lines.
RESULTS: Bufalin killed the TNBC cell line and its drug-resistant cell lines in a dose/time-dependent manner (all P<0.01). After treatment with bufalin for 24 h, the adriamycin-resistant cell line showed a co-existing pattern of necroptosis and apoptosis. However, at 48 h, necroptosis was the main manifestation. After treatment with bufalin, the expressions of tumor necrosis factor α, phospho-tumor necrosis factor receptor 1, phospho-receptor interacting protein 1 and c-caspase 3 increased (all P<0.01), the killing effect of bufalin could be mostly inhibited by NEC-1, and by z-VAD-fmk (both P<0.01). Besides, the intracellular reactive oxygen species (ROS) levels increased considerably (P<0.01), the antioxidant N-acetyl cysteine or Nec-1 could inhibit the increase of ROS level and the killing effect of bufalin (all P<0.01). The adriamycin-resistant cell line exhibited necroptosis characteristic after 48 h of bufalin treatment under TEM.
CONCLUSIONS: Bufalin could induce necroptosis through RIP1/ROS-mediated pathway to kill the drug-resistant TNBC cell lines. This finding provides critical experimental data and theoretical basis for the clinical application of bufalin to overcome the difficulties in the treatment of TNBC.

Keywords:  bufalin; drug resistant; necroptosis; reactive oxygen species pathway; triple-negative breast cancer

DOI:  https://doi.org/10.1007/s11655-021-3458-7
Cancers (Basel). 2021 Nov 22. pii: 5849. [Epub ahead of print]13(22):

AKF-D52, a Synthetic Phenoxypyrimidine-Urea Derivative, Triggers Extrinsic/Intrinsic Apoptosis and Cytoprotective Autophagy in Human Non-Small Cell Lung Cancer Cells.

Hyo-Sun Gil, Jeong-Hun Lee, Ahmed K Farag, Ahmed H E Hassan, Kyung-Sook Chung, Jung-Hye Choi, Eun-Joo Roh, Kyung-Tae Lee.

  Previously, we discovered that 1-(3,5-dimethoxyphenyl)-3-(4-(3-methoxyphenoxy)-2-((4-morpholinophenyl)amino)pyrimidin-5-yl)urea (AKF-D52), a synthetic phenoxypyrimidine urea derivative, acts as a growth inhibitor of various cancer cell types. In this study, we elucidated the antiproliferative properties of AFK-D52 and underlying mechanisms in non-small cell lung cancer (NSCLC) cells and an A549 xenograft animal model. AKF-D52 was found to induce both caspase-dependent and -independent apoptotic cell death. Furthermore, the mitochondrial component of the AKF-D52-induced apoptosis mechanism involves a reduction in mitochondrial membrane potential and regulation in B cell lymphoma-2 family protein expression. Moreover, AKF-D52 activates the extrinsic pathway through up-regulated expression of death receptor 3 and Fas and then the formation of a death-inducing signaling complex. AKF-D52 also induced autophagy by increasing acidic vesicular organelle formation and microtubule-associated protein 1A/1B-light chain 3-II levels and reducing p62 levels. Notably, pretreatment with autophagy inhibitors enhanced AKF-D52-induced cell death, indicating that the induced autophagy is cytoprotective. AKF-D52 treatment also triggered reactive oxygen species (ROS) production in NSCLC cells, whereas the antioxidant α-tocopherol abolished AKF-D52-induced cell death. In a xenograft lung cancer mouse model, AKF-D52 administration attenuated tumor growth by inducing apoptosis and autophagy in tumor tissues. Collectively, our data indicate that AKF-D52-induced ROS production plays a role in mediating apoptosis and cytoprotective autophagy in NSCLC.

Keywords:  AKF-D52; apoptosis; autophagy; non-small cell lung cancer (NSCLC); reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cancers13225849
Antioxidants (Basel). 2021 Nov 22. pii: 1856. [Epub ahead of print]10(11):

Peroxiporins Are Induced upon Oxidative Stress Insult and Are Associated with Oxidative Stress Resistance in Colon Cancer Cell Lines.

Ana Čipak Gašparović, Lidija Milković, Claudia Rodrigues, Monika Mlinarić, Graça Soveral.

  Oxidative stress can induce genetic instability and change cellular processes, resulting in colorectal cancer. Additionally, adaptation of oxidative defense causes therapy resistance, a major obstacle in successful cancer treatment. Peroxiporins are aquaporin membrane channels that facilitate H2O2 membrane permeation, crucial for regulating cell proliferation and antioxidative defense. Here, we investigated four colon cancer cell lines (Caco-2, HT-29, SW620, and HCT 116) for their sensitivity to H2O2, cellular antioxidative status, and ROS intracellular accumulation after H2O2 treatment. The expression of peroxiporins AQP1, AQP3, and AQP5 and levels of NRF2, the antioxidant transcription factor, and PPARγ, a transcription factor that regulates lipid metabolism, were evaluated before and after oxidative insult. Of the four tested cell lines, HT-29 was the most resistant and showed the highest expression of all tested peroxiporins and the lowest levels of intracellular ROS, without differences in GSH levels, catalase activity, nor NF2 and PPARγ levels. Caco-2 shows high expression of AQP3 and similar resistance as HT-29. These results imply that oxidative stress resistance can be obtained by several mechanisms other than the antioxidant defense system. Regulation of intracellular ROS through modulation of peroxiporin expression may represent an additional strategy to target the therapy resistance of cancer cells.

Keywords:  NRF2; aquaporin; colon cancer cell line; oxidative stress

DOI:  https://doi.org/10.3390/antiox10111856
Pharmaceuticals (Basel). 2021 Nov 17. pii: 1169. [Epub ahead of print]14(11):

Cannabidiol Induces Cell Death in Human Lung Cancer Cells and Cancer Stem Cells.

Hussein Hamad, Birgitte Brinkmann Olsen.

  Currently, there is no effective therapy against lung cancer due to the development of resistance. Resistance contributes to disease progression, recurrence, and mortality. The presence of so-called cancer stem cells could explain the ineffectiveness of conventional treatment, and the development of successful cancer treatment depends on the targeting also of cancer stem cells. Cannabidiol (CBD) is a cannabinoid with anti-tumor properties. However, the effects on cancer stem cells are not well understood. The effects of CBD were evaluated in spheres enriched in lung cancer stem cells and adherent lung cancer cells. We found that CBD decreased viability and induced cell death in both cell populations. Furthermore, we found that CBD activated the effector caspases 3/7, increased the expression of pro-apoptotic proteins, increased the levels of reactive oxygen species, as well as a leading to a loss of mitochondrial membrane potential in both populations. We also found that CBD decreased self-renewal, a hallmark of cancer stem cells. Overall, our results suggest that CBD is effective against the otherwise treatment-resistant cancer stem cells and joins a growing list of compounds effective against cancer stem cells. The effects and mechanisms of CBD in cancer stem cells should be further explored to find their Achilles heel.

Keywords:  apoptosis; cancer stem cells; cannabidiol; lung cancer; reactive oxygen species

DOI:  https://doi.org/10.3390/ph14111169
Avicenna J Phytomed. 2021 Nov-Dec;11(6):11(6): 541-550

β-sitosterol induces reactive oxygen species-mediated apoptosis in human hepatocellular carcinoma cell line.

Mary J Ditty, Devaraj Ezhilarasan.

   Objective: It is of interest to investigate the anti-proliferative effect of β-sitosterol (BS) on human hepatocellular carcinoma (HepG2) cell line.
Materials and Methods: β-sitosterol treatments (0.6 and 1.2 mM/ml) were done in HepG2 and after 24 hr, cell viability was evaluated by MTT assay. Reactive oxygen species (ROS) accumulating potential of BS was assessed by dichloro-dihydro-fluorescein diacetate staining. Morphology related to apoptosis was investigated by acridine orange and ethidium bromide dual staining. Cytochrome c and caspase 3 expressions were evaluated by immunofluorescence and western blot analyses.
Results: β-sitosterol induced cytotoxicity (p<0.001) and intracellular ROS in HepG2 cells in a dose-dependent manner. BS treatments accumulated induced intracellular ROS accumulation which led to membrane damage and mitochondrial toxicity. At the molecular level, BS treatments induced cytochrome c release from mitochondria and enhanced the protein expressions (p<0.05 vs 0.6 mM/ml and p<0.001 vs 1.2 mM/ml) of both caspase 3 and cleaved caspase 3.
Conclusion: β-sitosterol induced ROS accumulation which plays a critical role in apoptosis via the intrinsic pathway in HepG2 cells. The present investigation paves the way for further in vivo studies.

Keywords:  Apoptosis; Caspase; Liver cancer; Reactive oxygen species; β-sitosterol

DOI:  https://doi.org/10.22038/AJP.2021.17746
J Inorg Biochem. 2021 Nov 11. pii: S0162-0134(21)00310-X. [Epub ahead of print]226 111663

Distinct mechanism of action for antitumoral neutral cyclometalated Pt(II)-complexes bearing antifungal imidazolyl-based drugs.

Natalia Fernández-Pampín, Mónica Vaquero, Tania Gil, Gustavo Espino, Darío Fernández, Begoña García, Natalia Busto.

  Three neutral Pt(II) complexes containing 1-Methylimidazole and the antifungal imidazolyl drugs Clotrimazole and Bifonazole have been prepared. The general formula of the new derivatives is [Pt(κ2-(C^N)Cl(L)], where C^N stands for ppy = 2-phenylpyridinate, and L = 1-Methylimidazole (MeIm) for [Pt-MeIm]; L = Clotrimazole (CTZ) for [Pt-CTZ] and L = Bifonazole (BFZ) for [Pt-BFZ]). The complexes have been completely characterized in solution and the crystal structures of [Pt-BFZ] and [Pt-CTZ] have been resolved. Complexes [Pt-MeIm] and [Pt-BFZ] present higher cytotoxicity than cisplatin in SW480 (colon adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian cancer) cell lines. [Pt-MeIm] shows the highest accumulation in A549 cells, in agreement with its inability to interact with serum albumin. By contrast, [Pt-CTZ] and [Pt-BFZ] interact with serum proteins, a fact that reduces their bioavailability. The strongest interaction with bovine serum albumin (BSA) is found for [Pt-BFZ], which is the least internalized inside the cells. All the complexes are able to covalently interact with DNA. The most cytotoxic complexes, [Pt-MeIm] and [Pt-BFZ] induce cellular accumulation in G0/G1 and apoptosis by a similar pathway, probably involving a reactive oxygen species (ROS) generation mechanism. [Pt-BFZ] turns out to be the most efficient complex regarding ROS generation and causes mitochondrial membrane depolarization, whereas [Pt-MeIm] induces the opposite effect, hyperpolarization of the mitochondrial membrane. On the contrary, the least cytotoxic complex, [Pt-CTZ] cannot block the cell cycle or generate ROS and the mechanism by which it induces apoptosis could be a different one.

Keywords:  Antitumoral; Bifonazole; Clotrimazole; Cyclometalated platinum(II) complexes; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.jinorgbio.2021.111663
Cancer Lett. 2021 Nov 22. pii: S0304-3835(21)00589-9. [Epub ahead of print]

The aryl-ureido fatty acid CTU activates endoplasmic reticulum stress and PERK/NOXA-mediated apoptosis in tumor cells by a dual mitochondrial-targeting mechanism.

Hassan Choucair, Md Khalilur Rahman, Balasubrahmanyam Umashankar, Yassir Al-Zubaidi, Kirsi Bourget, Yongjuan Chen, Colin Dunstan, Tristan Rawling, Michael Murray.

  The cancer cell mitochondrion is functionally different from that in normal cells and could be targeted to develop novel experimental therapeutics. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells. Here we show that CTU rapidly depolarized the inner mitochondrial membrane, selectively inhibited complex III of the electron transport chain and increased reactive oxygen species (ROS) production. From RNA-seq analysis, endoplasmic reticulum (ER)-stress was a major activated pathway in CTU-treated cells and in MDA-MB-231 tumor xenografts from CTU-treated nu/nu mice. Mitochondrion-derived ROS activated the PERK-linked ER-stress pathway and induced the BH3-only protein NOXA leading to outer mitochondrial membrane (OMM) disruption. The lipid peroxyl scavenger α-tocopherol attenuated CTU-dependent ER-stress and apoptosis which confirmed the critical role of ROS. Oleic acid protected against CTU-mediated apoptosis by activating Mcl-1 expression, which increased NOXA sequestration and prevented OMM disruption. Taken together, CTU both uncouples mitochondrial electron transport and activates ROS production which promotes ER-stress-dependent OMM disruption and tumor cell death. Dual-mitochondrial targeting agents like CTU offer a novel approach for development of new anti-cancer therapeutics.

Keywords:  Endoplasmic reticulum stress; Mitochondria; Pro-apoptotic agents; Reactive oxygen species; Ureido-fatty acids

DOI:  https://doi.org/10.1016/j.canlet.2021.11.022
Antioxidants (Basel). 2021 Nov 11. pii: 1801. [Epub ahead of print]10(11):

Tumour Microenvironment Stress Promotes the Development of Drug Resistance.

Nicole A Seebacher, Maria Krchniakova, Alexandra E Stacy, Jan Skoda, Patric J Jansson.

  Multi-drug resistance (MDR) is a leading cause of cancer-related death, and it continues to be a major barrier to cancer treatment. The tumour microenvironment (TME) has proven to play an essential role in not only cancer progression and metastasis, but also the development of resistance to chemotherapy. Despite the significant advances in the efficacy of anti-cancer therapies, the development of drug resistance remains a major impediment to therapeutic success. This review highlights the interplay between various factors within the TME that collectively initiate or propagate MDR. The key TME-mediated mechanisms of MDR regulation that will be discussed herein include (1) altered metabolic processing and the reactive oxygen species (ROS)-hypoxia inducible factor (HIF) axis; (2) changes in stromal cells; (3) increased cancer cell survival via autophagy and failure of apoptosis; (4) altered drug delivery, uptake, or efflux and (5) the induction of a cancer stem cell (CSC) phenotype. The review also discusses thought-provoking ideas that may assist in overcoming the TME-induced MDR. We conclude that stressors from the TME and exposure to chemotherapeutic agents are strongly linked to the development of MDR in cancer cells. Therefore, there remains a vast area for potential research to further elicit the interplay between factors existing both within and outside the TME. Elucidating the mechanisms within this network is essential for developing new therapeutic strategies that are less prone to failure due to the development of resistance in cancer cells.

Keywords:  cancer stem cells; drug resistance; reactive oxygen species; tumour microenvironmental stress

DOI:  https://doi.org/10.3390/antiox10111801
Free Radic Biol Med. 2021 Nov 20. pii: S0891-5849(21)00821-2. [Epub ahead of print]

FOXM1-mediated activation of phospholipase D1 promotes lipid droplet accumulation and reduces ROS to support paclitaxel resistance in metastatic cancer cells.

Xin Zhang, Chao Huang, Yue Yuan, Sanshan Jin, Jianping Zhao, Wei Zhang, Huifang Liang, Xiaoping Chen, Bixiang Zhang.

  Chemoresistance is a major challenge for the treatment of cancer with metastasis. We investigated the mechanisms of lipid metabolites involved in drug resistance. Here, metastatic cancer cells isolated from mouse models were resistant to paclitaxel treatment in vitro and in vivo when compared with parental cancer cells. FOXM1, an oncogenic transcriptional factor, was highly expressed in metastatic cancer cells, and overexpression of FOXM1 conferred parental cancer cells resistance to paclitaxel. Lipidomic analysis showed that FOXM1 increased unsaturated triglyceride (TG) and phosphatidylcholine (PC) abundance, which are the main components of lipid droplet (LD). Inhibition of LD formation sensitized cells to paclitaxel. Mechanistically, the enzyme phospholipase D1 (PLD1) was identified as a potential effector target of FOXM1. PLD1 promoted LD accumulation, which reduced the level of reactive oxygen species (ROS) and maintained endoplasmic reticulum (ER) homeostasis in resistant cells with the treatment of paclitaxel. Moreover, inhibition of PLD1 reversed FOXM1-conferred paclitaxel resistance in vitro and in vivo. This study, for the first time, reveals the role of FOXM1-mediated PLD1 in LD accumulation and paclitaxel resistance. Targeting PLD1 or LD formation may help reverse chemoresistance in metastatic cancer cells. Generally, our results identified FOXM1 as a driver of paclitaxel resistance via activation of PLD1 to promote of LD accumulation, which contributes to the maintenace of ER homeostasis when metastatic cancer cells are confronted with ROS induced by paclitaxel.

Keywords:  Chemoresistance; ER homeostasis; FOXM1; Lipid droplet; Phospholipase D1; ROS

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.11.024
Antioxidants (Basel). 2021 Nov 03. pii: 1757. [Epub ahead of print]10(11):

Effects of Iodonium Analogs on Nadph Oxidase 1 in Human Colon Cancer Cells.

Krishnendu K Roy, Jiamo Lu, James H Doroshow.

  Recent studies suggest that of the molecules postulated to function as inhibitors of the NADPH oxidase family of enzymes iodonium analogs known to broadly interfere with flavin dehydrogenase function demonstrate mechanistic validity as NADPH oxidase poisons. In recent work, we have produced a series of novel iodonium compounds as putative inhibitors of these oxidases. To evaluate the potential utility of two novel molecules with favorable chemical properties, NSC 740104 and NSC 751140, we compared effects of these compounds to the two standard inhibitors of this class, diphenyleneiodonium and di-2-thienyliodonium, with respect to antiproliferative, cell cycle, and gene expression effects in human colon cancer cells that require the function of NADPH oxidase 1. Both new agents blocked NADPH oxidase-related reactive oxygen production, inhibited tumor cell proliferation, produced a G1/S block in cell cycle progression, and inhibited NADPH oxidase 1 expression at the mRNA and protein levels at low nM concentrations in a fashion similar to or better than the parent molecules. These studies suggest that NSC 740104 and NSC 751140 should be developed further as mechanistic tools to better understand the role of NADPH oxidase inhibition as an approach to the development of novel therapeutic agents for colon cancer.

Keywords:  NADPH oxidase 1 (NOX1); di-2-thienyliodonium (DTI); diphenyleneiodonium (DPI); hydrogen peroxide (H2O2); reactive oxygen species (ROS); superoxide (O2●−)

DOI:  https://doi.org/10.3390/antiox10111757
Biology (Basel). 2021 Nov 09. pii: 1156. [Epub ahead of print]10(11):

The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells.

Charlotte Orre, Xavier Dieu, Jordan Guillon, Naïg Gueguen, Seyedeh Tayebeh Ahmadpour, Jean-François Dumas, Salim Khiati, Pascal Reynier, Guy Lenaers, Olivier Coqueret, Arnaud Chevrollier, Delphine Mirebeau-Prunier, Valérie Desquiret-Dumas.

  Despite improvements in therapeutic strategies for treating breast cancers, tumor relapse and chemoresistance remain major issues in patient outcomes. Indeed, cancer cells display a metabolic plasticity allowing a quick adaptation to the tumoral microenvironment and to cellular stresses induced by chemotherapy. Recently, long non-coding RNA molecules (lncRNAs) have emerged as important regulators of cellular metabolic orientation. In the present study, we addressed the role of the long non-coding RNA molecule (lncRNA) SAMMSON on the metabolic reprogramming and chemoresistance of MCF-7 breast cancer cells resistant to doxorubicin (MCF-7dox). Our results showed an overexpression of SAMMSON in MCF-7dox compared to doxorubicin-sensitive cells (MCF-7). Silencing of SAMMSON expression by siRNA in MCF-7dox cells resulted in a metabolic rewiring with improvement of oxidative metabolism, decreased mitochondrial ROS production, increased mitochondrial replication, transcription and translation and an attenuation of chemoresistance. These results highlight the role of SAMMSON in the metabolic adaptations leading to the development of chemoresistance in breast cancer cells. Thus, targeting SAMMSON expression levels represents a promising therapeutic route to circumvent doxorubicin resistance in breast cancers.

Keywords:  SAMMSON; breast cancer; complex I; long non-coding RNA; metabolism; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.3390/biology10111156
Biomolecules. 2021 Nov 10. pii: 1666. [Epub ahead of print]11(11):

An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival.

Iiro Taneli Helenius, Hanumantha Rao Madala, Jing-Ruey Joanna Yeh.

  A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate-aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation.

Keywords:  GOT1; alpha-ketoglutarate; asparagine; aspartate; cancer metabolism; glutaminase; hypoxia; mitochondrial DNA mutation; mitochondrial respiration; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biom11111666
Cancers (Basel). 2021 Nov 18. pii: 5791. [Epub ahead of print]13(22):

Oxidative Stress and Autophagy as Key Targets in Melanoma Cell Fate.

Elisabetta Catalani, Matteo Giovarelli, Silvia Zecchini, Cristiana Perrotta, Davide Cervia.

  Melanoma originates from the malignant transformation of melanocytes and is one of the most aggressive forms of cancer. The recent approval of several drugs has increased the chance of survival although a significant subset of patients with metastatic melanoma do not show a long-lasting response to these treatments. The complex cross-talk between oxidative stress and the catabolic process autophagy seems to play a central role in all aspects of melanoma pathophysiology, from initiation to progression and metastasis, including drug resistance. However, determining the fine role of autophagy in cancer death and in response to redox disruption is still a fundamental challenge in order to advance both basic and translational aspects of this field. In order to summarize the interactions among reactive oxygen and nitrogen species, autophagy machinery and proliferation/growth/death/apoptosis/survival, we provide here a narrative review of the preclinical evidence for drugs/treatments that modulate oxidative stress and autophagy in melanoma cells. The significance and the potential for pharmacological targeting (also through multiple and combination approaches) of these two different events, which can contribute independently or simultaneously to the fate of melanoma, may help to define new processes and their interconnections underlying skin cancer biology and unravel new reliable approaches.

Keywords:  anti and pro-oxidants; autophagosomes; autophagy modulators; cell death and survival; reactive oxygen and nitrogen species; skin cancer

DOI:  https://doi.org/10.3390/cancers13225791
Acta Pharmacol Sin. 2021 Nov 22.

The double faced role of xanthine oxidoreductase in cancer.

Man-Man Chen, Ling-Hua Meng.

  Xanthine oxidoreductase (XOR) is a critical, rate-limiting enzyme that controls the last two steps of purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. It also produces reactive oxygen species (ROS) during the catalytic process. The enzyme is generally recognized as a drug target for the therapy of gout and hyperuricemia. The catalytic products uric acid and ROS act as antioxidants or oxidants, respectively, and are involved in pro/anti-inflammatory actions, which are associated with various disease manifestations, including metabolic syndrome, ischemia reperfusion injury, cardiovascular disorders, and cancer. Recently, extensive efforts have been devoted to understanding the paradoxical roles of XOR in tumor promotion. Here, we summarize the expression of XOR in different types of cancer and decipher the dual roles of XOR in cancer by its enzymatic or nonenzymatic activity to provide an updated understanding of the mechanistic function of XOR in cancer. We also discuss the potential to modulate XOR in cancer therapy.

Keywords:  ROS; cancer therapy; uric acid; xanthine oxidoreductase (XOR)

DOI:  https://doi.org/10.1038/s41401-021-00800-7
Biomedicines. 2021 Oct 24. pii: 1527. [Epub ahead of print]9(11):

Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells.

Jing-Yan Gao, Chih-Shiang Chang, Jin-Cherng Lien, Ting-Wei Chen, Jing-Lan Hu, Jing-Ru Weng.

  Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.

Keywords:  ROS; apoptosis; cell cycle arrest; hepatocellular carcinoma; tryptanthrin

DOI:  https://doi.org/10.3390/biomedicines9111527
Cells. 2021 Nov 11. pii: 3131. [Epub ahead of print]10(11):

The TRPA1 Channel Amplifies the Oxidative Stress Signal in Melanoma.

Francesco De Logu, Daniel Souza Monteiro de Araujo, Filippo Ugolini, Luigi Francesco Iannone, Margherita Vannucchi, Francesca Portelli, Lorenzo Landini, Mustafa Titiz, Vincenzo De Giorgi, Pierangelo Geppetti, Daniela Massi, Romina Nassini.

  Macrophages (MΦs) and reactive oxygen species (ROS) are implicated in carcinogenesis. The oxidative stress sensor, transient receptor potential ankyrin 1 (TRPA1), activated by ROS, appears to contribute to lung and breast cancer progression. Although TRPA1 expression has been reported in melanoma cell lines, and oxidative stress has been associated with melanocytic transformation, their role in melanoma remains poorly known. Here, we localized MΦs, the final end-product of oxidative stress, 4-hydroxynonenal (4-HNE), and TRPA1 in tissue samples of human common dermal melanocytic nevi, dysplastic nevi, and thin (pT1) and thick (pT4) cutaneous melanomas. The number (amount) of intratumoral and peritumoral M2 MΦs and 4-HNE staining progressively increased with tumor severity, while TRPA1 expression was similar in all samples. Hydrogen peroxide (H2O2) evoked a TRPA1-dependent calcium response in two distinct melanoma cell lines (SK-MEL-28 and WM266-4). Furthermore, H2O2 induced a TRPA1-dependent H2O2 release that was prevented by the TRPA1 antagonist, A967079, or Trpa1 gene silencing (siRNA). ROS release from infiltrating M2 MΦs may target TRPA1-expressing melanoma cells to amplify the oxidative stress signal that affects tumor cell survival and proliferation.

Keywords:  TRPA1; image analysis; macrophages; melanoma; oxidative stress

DOI:  https://doi.org/10.3390/cells10113131
J Nat Prod. 2021 Nov 21.

A Derivative of Piperlongumine and Ligustrazine as a Potential Thioredoxin Reductase Inhibitor in Drug-Resistant Hepatocellular Carcinoma.

Jianqiang Qian, Zhongyuan Xu, Peng Zhu, Chi Meng, Yun Liu, Wenpei Shan, Ang He, Yipeng Gu, Fansheng Ran, Yanan Zhang, Yong Ling.

The natural products piperlongumine (1) and ligustrazine (2) have been reported to exert antiproliferative effects against various types of cancer cells by up-regulating the level of reactive oxidative species (ROS). However, the moderate activities of 1 and 2 limit their application. To improve their potential antitumor activity, novel piperlongumine/ligustrazine derivatives were designed and prepared, and their potential pharmacological effects were determined in vitro and in vivo. Among the derivatives obtained, 11 exerted more prominent inhibitory activities against proliferation of drug-sensitive/-resistant cancer cells with lower IC50 values than 1. Particularly, the IC50 value of 11 against drug-resistant Bel-7402/5-FU cells was 0.9 μM, which was about 9-fold better than that of 1 (IC50 value of 8.4 μM). Mechanistic studies showed that 11 demonstrated thioredoxin reductase (TrxR) inhibitory activity, increase of ROS levels, decrease of mitochondrial transmembrane potential levels, and occurrence of DNA damage and autophagy, in a dose-dependent manner, via regulation of DNA damage protein H2AX and autophagy-associated proteins LC3, beclin-1, and p62 in drug-resistant Bel-7402/5-FU cells. Finally, compound 11 at 5 mg/kg displayed potent antitumor activity in vivo with tumor suppression of 76% (w/w). Taken together, compound 11 may represent a promising candidate drug for the chemotherapy of drug-resistant hepatocellular carcinoma and warrant more intensive study.

DOI: https://doi.org/10.1021/acs.jnatprod.1c00618
Mol Biol Rep. 2021 Nov 24.

Antineoplastic effectiveness of silver nanoparticles synthesized from Onopordum acanthium L. extract (AgNPs-OAL) toward MDA-MB231 breast cancer cells.

Romina Delalat, Seyed Ataollah Sadat Shandiz, Bahareh Pakpour.

   BACKGROUND: The present research was done to investigate the anticancer properties of silver nanoparticles (AgNPs) fabricated using bioactive extract of Onopordum acanthium L. (AgNPs-OAL) against breast cancer cells MDA_MB231 in vitro.
METHODS: The determination studies of AgNPs-OAL were confirmed by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) analysis. Interestingly, the FESEM image observed the spherical shape of AgNPs-OAL with the range of 1-100 nm.
RESULTS: As AgNP-OAL exhibited significant cytotoxicity properties on breast cancer MDA_MB231 cells with IC50 values of 66.04 µg/mL, while lowing toxicity toward normal human embryonic kidney 293 (HEK293) cells with IC50 values of 101.04 µg/mL was evaluated. Further, up-regulation of apoptotic Bax and CAD gene expressions were confirmed by quantitative real-time reverse transcription-PCR (qRT-PCR) technique results. Moreover, enhanced cell cycle population (sub-G1), annexin V/PI staining, acridine orange and ethidium bromide (AO/EB) staining, Hoescht 33,258 dye, and generation of reactive oxygen species were observed in AgNP-OAL-treated MDA_MB231 cancer cells.
CONCLUSIONS: The green-synthesized AgNP-OAL has promising anticancer efficiency that can trigger apoptosis pathways in the MDA_MB231 breast cancer cells.

Keywords:  Anticancer; Apoptosis; Reactive oxygen species; Silver nanoparticles

DOI:  https://doi.org/10.1007/s11033-021-06936-3
Biomed Mater. 2021 Nov 26.

Selective cytotoxicity mechanisms and biodistribution of diamond nanoparticles on the skin cancer in C57 mouse.

Elham Moradi, Parvaneh Naserzadeh, Peiman Brouki Millan, Behnaz Ashtari.

  The cytotoxicity of diamond nanoparticles (DNs) to various cell lines has been on focus by numerous scientists. The cellular toxicity system of DNs has not been fully understood or explained in skin cancer, at this point. This research was carried out to discover and reveal the potential impacts of DNs on the secluded brain, heart, liver, kidney, and skin in addition to evaluation of their cytotoxicity mechanism under test conditions. Their biological activities, for example cell viability, the level of reactive oxygen species (ROS), lipid peroxidation, cytochrome c release and Apoptosis/Necrosis were evaluated. Additionally, the bio-distribution of these nanomaterials in tissues was examined in the C57 mouse. Relying on the findings of the investigation, DNs were found to increase the ROS level, MDA content, release of cytochrome c, and cell death in skin significantly compared to other groups. In the C57 mouse, DNs were observed to have accumulated in skin tissue more intensively than they did in other organs. The present study presents for the the proof that DNs can completely induce cell death signaling in skin cancer without bringing about a high cytotoxicity in other tissues. Results suggest that DNs can be valuable in recognition of skin cancer.

Keywords:  Diamond Nanoparticles; Reactive Oxygen Species; Skin cancer; cell death signaling; cytotoxicity; stress oxidative

DOI:  https://doi.org/10.1088/1748-605X/ac3d99
PLoS One. 2021 ;16(11): e0260400

Activated heme synthesis regulates glycolysis and oxidative metabolism in breast and ovarian cancer cells.

Pritpal Kaur, Shreya Nagar, Madhura Bhagwat, Mohammad Uddin, Yan Zhu, Ivana Vancurova, Ales Vancura.

Heme is an essential cofactor for enzymes of the electron transport chain (ETC) and ATP synthesis in mitochondrial oxidative phosphorylation (OXPHOS). Heme also binds to and destabilizes Bach1, a transcription regulator that controls expression of several groups of genes important for glycolysis, ETC, and metastasis of cancer cells. Heme synthesis can thus affect pathways through which cells generate energy and precursors for anabolism. In addition, increased heme synthesis may trigger oxidative stress. Since many cancers are characterized by a high glycolytic rate regardless of oxygen availability, targeting glycolysis, ETC, and OXPHOS have emerged as a potential therapeutic strategy. Here, we report that enhancing heme synthesis through exogenous supplementation of heme precursor 5-aminolevulinic acid (ALA) suppresses oxidative metabolism as well as glycolysis and significantly reduces proliferation of both ovarian and breast cancer cells. ALA supplementation also destabilizes Bach1 and inhibits migration of both cell types. Our data indicate that the underlying mechanisms differ in ovarian and breast cancer cells, but involve destabilization of Bach1, AMPK activation, and induction of oxidative stress. In addition, there appears to be an inverse correlation between the activity of oxidative metabolism and ALA sensitivity. Promoting heme synthesis by ALA supplementation may thus represent a promising new anti-cancer strategy, particularly in cancers that are sensitive to altered redox signaling, or in combination with strategies that target the antioxidant systems or metabolic weaknesses of cancer cells.

DOI: https://doi.org/10.1371/journal.pone.0260400
Nanomaterials (Basel). 2021 Oct 28. pii: 2875. [Epub ahead of print]11(11):

Smart Design of Mitochondria-Targeted and ROS-Responsive CPI-613 Delivery Nanoplatform for Bioenergetic Pancreatic Cancer Therapy.

Yi-Mei Zhang, Meng Xia, Rui Ao, Li-Xia Gao, Yan Tang, Jiu-Hong Huang, Ya-Fei Luo, Zhong-Zhu Chen, Bo-Chu Wang, Zheng Huang.

  Mitochondria, as the powerhouse of most cells, are not only responsible for the generation of adenosine triphosphate (ATP) but also play a decisive role in the regulation of apoptotic cell death, especially of cancer cells. Safe potential delivery systems which can achieve organelle-targeted therapy are urgently required. In this study, for effective pancreatic cancer therapy, a novel mitochondria-targeted and ROS-triggered drug delivery nanoplatform was developed from the TPP-TK-CPI-613 (TTCI) prodrug, in which the ROS-cleave thioketal functions as a linker connecting mitochondrial targeting ligand TPP and anti-mitochondrial metabolism agent CPI-613. DSPE-PEG2000 was added as an assistant component to increase accumulation in the tumor via the EPR effect. This new nanoplatform showed effective mitochondrial targeting, ROS-cleaving capability, and robust therapeutic performances. With active mitochondrial targeting, the formulated nanoparticles (TTCI NPs) demonstrate much higher accumulation in mitochondria, facilitating the targeted delivery of CPI-613 to its acting site. The results of in vitro antitumor activity and cell apoptosis revealed that the IC50 values of TTCI NPs in three types of pancreatic cancer cells were around 20~30 µM, which was far lower than those of CPI-613 (200 µM); 50 µM TTCI NPs showed an increase in apoptosis of up to 97.3% in BxPC3 cells. Therefore, this mitochondria-targeted prodrug nanoparticle platform provides a potential strategy for developing safe, targeting and efficient drug delivery systems for pancreatic cancer therapy.

Keywords:  CPI-613; ROS-responsive; drug delivery; mitochondria-targeting; nanoparticles; pancreatic cancer therapy

DOI:  https://doi.org/10.3390/nano11112875
ACS Appl Mater Interfaces. 2021 Nov 20.

Pulmonary Delivery of Reactive Oxygen Species/Glutathione-Responsive Paclitaxel Dimeric Nanoparticles Improved Therapeutic Indices against Metastatic Lung Cancer.

Xidong Tian, Hriday Bera, Xiong Guo, Ruizhao Xu, Jin Sun, Zhonggui He, Dongmei Cun, Mingshi Yang.

  Chemotherapeutics often failed to elicit optimal antitumor responses against lung cancer due to their limited exposure and accumulation in tumors. To achieve an effective therapeutic outcome of paclitaxel (PTX) against metastatic lung cancer with attenuated systemic and local toxicities, pulmonary delivery of redox-responsive PTX dimeric nanoparticles (NPs) was introduced. PTX dimers conjugated through variable lengths of diacid linkers containing disulfide bonds (-SS-) (i.e., α-PTX-SS-PTX, β-PTX-SS-PTX, and γ-PTX-SS-PTX) were initially synthesized and were subsequently self-assembled into uniform nanosized particles in the presence of vitamin E TPGS with high drug loading capacity (DE > 97%). Among various redox-sensitive scaffolds, β-PTX-SS-PTX NPs exhibited an optimal reactive oxygen species/glutathione-responsive drug release behavior, causing a lower local toxicity profile of PTX in the lungs. The scaffolds also demonstrated excellent colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between cancer and healthy cells. Further, they depicted an improved lung retention as compared to the control nanovesicles (β-PTX-CC-PTX) devoid of the redox-sensitive disulfide motif. In the B16F10 melanoma metastatic lung cancer mouse model, intratracheally delivered β-PTX-SS-PTX NPs exhibited a stronger anticancer potential with reduced systemic toxicity as compared to Taxol intravenous injection containing an equivalent PTX dose. The PTX dimeric NPs could also dramatically reduce the local toxicity relative to Taxol following their pulmonary delivery. Thus, this study presents redox-responsive PTX dimeric NPs as a promising nanomedicine for improved therapeutic efficacy against metastatic lung cancer.

Keywords:  disulfide bonds; glutathione; inhaled chemotherapy; paclitaxel dimer; pulmonary toxicity; reactive oxygen species

DOI:  https://doi.org/10.1021/acsami.1c16351
Biology (Basel). 2021 Nov 08. pii: 1148. [Epub ahead of print]10(11):

Internalized Nanoceria Modify the Radiation-Sensitivity Profile of MDA MB231 Breast Carcinoma Cells.

Emory Bibb, Noura Alajlan, Saad Alsuwailem, Benjamin Mitchell, Amy Brady, Muhammad Maqbool, Remo George.

  Owing to its unique redox properties, cerium oxide (nanoceria) nanoparticles have been shown to confer either radiosensitization or radioprotection to human cells. We investigated nanoceria's ability to modify cellular health and reactive oxygen species (ROS) at various absorbed doses (Gray) of ionizing radiation in MDA-MB231 breast carcinoma cells. We used transmission electron microscopy to visualize the uptake and compartmental localization of nanoceria within cells at various treatment concentrations. The effects on apoptosis and other cellular health parameters were assessed using confocal fluorescence imaging and flow cytometry without and with various absorbed doses of ionizing radiation, along with intracellular ROS levels. Our results showed that nanoceria were taken up into cells mainly by macropinocytosis and segregated into concentration-dependent large aggregates in macropinosomes. Confocal imaging and flow cytometry data showed an overall decrease in apoptotic cell populations in proportion to increasing nanoparticle concentrations. This increase in cellular health was observed with a corresponding reduction in ROS at all tested absorbed doses. Moreover, this effect appeared pronounced at lower doses compared to unirradiated or untreated populations. In conclusion, internalized nanoceria confers radioprotection with a corresponding decrease in ROS in MDA-MB231 cells, and this property confers significant perils and opportunities when utilized in the context of radiotherapy.

Keywords:  MDA MB231 cells; apoptosis; cerium oxide nanoparticles; macropinocytosis; macropinosomes; radiation protection; radiosensitivity; reactive oxygen species

DOI:  https://doi.org/10.3390/biology10111148
Molecules. 2021 Nov 21. pii: 7037. [Epub ahead of print]26(22):

The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90.

Kuan-Chih Wang, Mei-Chin Lu, Kai-Cheng Hsu, Mohamed El-Shazly, Shou-Ping Shih, Ssu-Ting Lien, Fu-Wen Kuo, Shyh-Chyun Yang, Chun-Lin Chen, Yu-Chen S H Yang.

  Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC50 values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 μM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 μg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.

Keywords:  Heat shock protein 90 (HSP-90); anticancer; apoptosis; polycyclic quinone; reactive oxygen species (ROS); topoisomerase; xestoquinone

DOI:  https://doi.org/10.3390/molecules26227037
Int J Mol Sci. 2021 Nov 22. pii: 12593. [Epub ahead of print]22(22):

The Preliminary Study on the Proapoptotic Effect of Reduced Graphene Oxide in Breast Cancer Cell Lines.

Rafał Krętowski, Agata Jabłońska-Trypuć, Marzanna Cechowska-Pasko.

  Breast cancer is the most common cancer diagnosed in women, however traditional therapies have several side effects. This has led to an urgent need to explore novel drug approaches to treatment strategies such as graphene-based nanomaterials such as reduced graphene oxide (rGO). It was noticed as a potential drug due to its target selectivity, easy functionalisation, chemisensitisation, and high drug-loading capacity. rGO is widely used in many fields, including biological and biomedical, due to its unique physicochemical properties. However, the possible mechanisms of rGO toxicity remain unclear. In this paper, we present findings on the cytotoxic and antiproliferative effects of rGO and its ability to induce oxidative stress and apoptosis of breast cancer cell lines. We indicate that rGO induced time- and dose-dependent cytotoxicity in MDA-MB-231 and ZR-75-1 cell lines, but not in T-47D, MCF-7, Hs 578T cell lines. In rGO-treated MDA-MB-231 and ZR-75-1 cell lines, we noticed increased induction of apoptosis and necrosis. In addition, rGO has been found to cause oxidative stress, reduce proliferation, and induce structural changes in breast cancer cells. Taken together, these studies provide new insight into the mechanism of oxidative stress and apoptosis in breast cancer cells.

Keywords:  apoptosis; breast cancer; oxidative stress; proliferation; rGO

DOI:  https://doi.org/10.3390/ijms222212593
Anal Chem. 2021 Nov 20.

Deep-Tissue Fluorescence Imaging Study of Reactive Oxygen Species in a Tumor Microenvironment.

Chuanchen Wu, Yuantao Mao, Xin Wang, Ping Li, Bo Tang.

Tumor microenvironment (TME) is the survival environment for tumor cells to proliferate and metastasize in deep tissue. TME contains tumor cells, immune cells, stromal cells and a variety of active molecules including reactive oxygen species (ROS). Inside the TME, ROS regulate the oxidation-reduction (redox) homeostasis and promote oxidative stress. Due to the rapid proliferation ability and specific metabolic patterns of the TME, ROS pervade virtually all complex physiological processes and play irreplaceable roles in protein modification, signal transduction, metabolism, and energy production in various tumors. Therefore, measurements of the dynamically, multicomponent simultaneous changes of ROS in the TME are of great significance to reveal the detailed proliferation and metastasis mechanisms of the tumor. Near-infrared (NIR) and two-photon (TP) fluorescence imaging techniques possess real-time, dynamic, highly sensitive, and highly signal-to-noise ratios with deep tissue penetration abilities. With the rationally designed probes, the NIR and TP fluorescence imaging techniques have been widely used to reveal the mechanisms of how ROS regulates and constructs complex signals and metabolic networks in TME. Therefore, we summarize the design principles and performances of NIR and TP fluorescence imaging of ROS in the TME in the last four years, as well as discuss the advantages and potentials of these works. This Review can provide guidance and prospects for future research work on TME and facilitate the development of antitumor drugs.

DOI: https://doi.org/10.1021/acs.analchem.1c03104