bims-rehoca 2022-01-09 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2022–01–09
nineteen papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.
Nisin induces apoptosis in cervical cancer cells via reactive oxygen species generation and mitochondrial membrane potential changes.
Enhanced Intracellular Reactive Oxygen Species by Photodynamic Therapy Effectively Promotes Chemoresistant Cell Death.
Small-molecule NSC59984 induces mutant p53 degradation through a ROS-ERK2-MDM2 axis in cancer cells.
Reactive oxygen species: Key players in the anticancer effects of apigenin?
Atom-precise fluorescent copper cluster for tumor microenvironment targeting and transient chemodynamic cancer therapy.
Ferroptosis-Inducing Nanomedicine for Cancer Therapy.
Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling.
Investigation of the Genotoxic, Cytotoxic, Apoptotic, and Oxidant Effects of Olive Leaf Extracts on Liver Cancer Cell Lines.
ROS-Mediated Anti-Angiogenic Activity of Cerium Oxide Nanoparticles in Melanoma Cells.
Ultrasound-Enhanced Reactive Oxygen Species Responsive Charge-Reversal Polymeric Nanocarriers for Efficient Pancreatic Cancer Gene Delivery.
Regulation of reactive oxygen species by phytochemicals for the management of cancer and diabetes.
Hybrid Carbon Dot Assembly as a Reactive Oxygen Species Nanogenerator for Ultrasound-Assisted Tumor Ablation.
Anticancer potential and through study of the cytotoxicity mechanism of ionic liquids that are based on the trifluoromethanesulfonate and bis(trifluoromethylsulfonyl)imide anions.
Malignant growth of arsenic-transformed cells depends on activated Akt induced by reactive oxygen species.
A novel halogenated adenosine analog 5'-BrDA displays potent toxicity against colon cancer cells in vivo and in vitro.
Role of ferroptosis in promoting cardiotoxicity induced by Imatinib Mesylate via down-regulating Nrf2 pathways in vitro and in vivo.
Biguanide MC001, a dual inhibitor of OXPHOS and glycolysis, shows enhanced anti-tumor activity without increasing lactate production.
Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.

Biomaterials. 2021 Dec 30. pii: S0142-9612(21)00714-6. [Epub ahead of print]281 121358

Harnessing in situ glutathione for effective ROS generation and tumor suppression via nanohybrid-mediated catabolism dynamic therapy.

Si-Yuan Peng, Xin-Hua Liu, Qi-Wen Chen, Yun-Jian Yu, Miao-Deng Liu, Xian-Zheng Zhang.

  The overexpression of glutathione (GSH) in cancer cells has long been regarded as the primary obstacle for reactive oxygen species (ROS)-involved anti-tumor therapies. To solve this issue, a ferric ion and selenite-codoped calcium phosphate (Fe/Se-CaP) nanohybrid here is fabricated to catabolize endogenous GSH, instead of directly deleting it, to trigger a ROS storm for tumor suppression. The selenite component in Fe/Se-CaP can catabolize GSH to superoxide anion (O2•-) and hydroxyl radicals (•OH) via cascade catalytic reactions, elevating oxidative stress while destroying antioxidant system. The doped Fe can further catalyze the soaring hydrogen peroxide (H2O2) originated from O2•- to •OH via Fenton reactions. Collectively, Fe/Se-CaP mediated self-augmented catabolism dynamic therapy finally induces apoptosis of cancer cells owing to the significant rise of ROS and, combined with CaP adjuvant, evokes adaptive immune responses to suppress tumor progression, providing an innovative train of thought for ROS-involved anti-tumor therapies.

Keywords:  Biocascade conversion; Glutathione catabolism; Immune response; Reactive oxygen species; Tumor therapy

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121358
Biochem Cell Biol. 2022 Jan 05.

Nisin induces apoptosis in cervical cancer cells via reactive oxygen species generation and mitochondrial membrane potential changes.

Houri Sadri, Mahmoud Aghaei, Vajihe Akbari.

Nisin, an antimicrobial peptide produced by Lactococcus lactis, is widely used as a safe food preservative and has been recently attracting the attention of many researchers as a potential anticancer agent. The cytotoxicity of nisin against HeLa, OVCAR-3, SK-OV-3, and HUVEC cells was evaluated using MTT assay. The apoptotic effect of nisin was identified by Annexin-V/propidium iodide assay, and then it was further confirmed by western blotting analysis, mitochondrial membrane potential (ΔΨm) analysis, and reactive oxygen species (ROS) assay. The MTT assay showed concentration-dependent cytotoxicity of nisin towards cancer cell lines, with the IC50 values of 11.5-23 µM, but less toxicity against normal endothelial cells. Furthermore, treatment of cervical cancer cells with 12 µM nisin significantly (P<0.05) increased the Bax/Bcl-2 ratio (4.9-fold), reduced ΔΨm (70%), and elevated ROS levels (1.7-fold). These findings indicated that nisin might have anticancer and apoptogenic activities through mitochondrial dysfunction and oxidative stress damage in cervical cancer cells.

DOI: https://doi.org/10.1139/bcb-2021-0225
Int J Biol Sci. 2022 ;18(1): 374-385

Enhanced Intracellular Reactive Oxygen Species by Photodynamic Therapy Effectively Promotes Chemoresistant Cell Death.

Xiaolin Xu, Chenglong Wang, Peipei Zhang, Xuzhu Gao, Wencai Guan, Fanchen Wang, Xin Li, Jia Yuan, Hongjing Dou, Guoxiong Xu.

  Anti-cancer chemo-drugs can cause a rapid elevation of intracellular reactive oxygen species (ROS) levels. An imbalance in ROS production and elimination systems leads to cancer cell resistance to chemotherapy. This study aimed to evaluate the mechanism and effect of ROS on multidrug resistance in various human chemoresistant cancer cells by detecting the changes in the amount of ROS, the expression of ROS-related and glycolysis-related genes, and cell death. We found that ROS was decreased while oxidative phosphorylation was increased in chemoresistant cells. We verified that the chemoresistance of cancer cells was achieved in two ways. First, chemoresistant cells preferred oxidative phosphorylation instead of anaerobic glycolysis for energy generation, which increased ATPase activity and produced much more ATP to provide energy. Second, ROS-scavenging systems were enhanced in chemoresistant cancer cells, which in turn decreased ROS amount and thus inhibited chemo-induced cell death. Our in vitro and in vivo photodynamic therapy further demonstrated that elevated ROS production efficiently inhibited chemo-drug resistance and promoted chemoresistant cell death. Taken together, targeting ROS systems has a great potential to treat cancer patients with chemoresistance.

Keywords:  Chemoresistance; ROS; glycolysis; malignant tumor; oxidative phosphorylation; photodynamic therapy

DOI:  https://doi.org/10.7150/ijbs.66602
Mol Cancer Res. 2022 Jan 06. pii: molcanres.MCR-21-0149-A.2021. [Epub ahead of print]

Small-molecule NSC59984 induces mutant p53 degradation through a ROS-ERK2-MDM2 axis in cancer cells.

Shengliang Zhang, Lanlan Zhou, Wafik S El-Deiry.

Increased reactive oxygen species (ROS) and hyper-stabilized mutant p53 are common in cancer. Hyper-stabilized mutant p53 contributes to its gain-of-function (GOF) which confers resistance to chemo- and radio-therapy. Targeting mutant p53 degradation is a promising cancer therapeutic strategy. We used a small-molecule NSC59984 to explore elimination of mutant p53 in cancer cells, and identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for induction of mutant p53 degradation in cancer cells. NSC59984 treatment promotes a constitutive phosphorylation of ERK2 via ROS in cancer cells. The NSC59984-sustained ERK2 activation is required for MDM2 phosphorylation at serine-166. NSC59984 enhances phosphorylated-MDM2 binding to mutant p53, which leads to mutant p53 ubiquitination and degradation. High cellular ROS increases the efficacy of NSC59984 targeting mutant p53 degradation and anti-tumor effects. Our data suggest that mutant p53 stabilization has a vulnerability under high ROS cellular conditions, which can be exploited by compounds to target mutant p53 protein degradation through the activation of a ROS-ERK2-MDM2 axis in cancer cells. Implications: An inducible ROS-ERK2-MDM2 axis exposes a vulnerability in mutant p53 stabilization and can be exploited by small molecule compounds to induce mutant p53 degradation for cancer therapy.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0149
J Food Biochem. 2022 Jan 07. e14060

Reactive oxygen species: Key players in the anticancer effects of apigenin?

Omolola R Oyenihi, Ayodeji B Oyenihi, Toyin D Alabi, Oluwatosin G Tade, Anne A Adeyanju, Oluwafemi O Oguntibeju.

  Reactive oxygen species (ROS) exhibit a double-edged sword in cancer-hence their modulation has been an attractive strategy in cancer prevention and therapy. The abundance of scientific information on the pro-oxidant effects of apigenin in cancer cells suggests the crucial role of ROS in its mechanisms of action. Although apigenin is known to enhance the cellular ROS levels to cytotoxic degrees in cancer cells in vitro, it remains to be determined if these pro-oxidant effects prevail or are relevant in experimental tumor models and clinical trials. Here, we critically examine the pro-oxidant and antioxidant effects of apigenin in cancer to provide insightful perspectives on the association between its ROS-modulating action and anticancer potential. We also discussed these effects in a cell/tissue type-specific context to highlight the factors influencing the switch between antioxidant and pro-oxidant effects. Finally, we raised some questions that need addressing for the potential translation of these studies into clinical applications. Further research into this duality in oxidant actions of apigenin, especially in vivo, may enable better exploitation of its anticancer potential. PRACTICAL APPLICATION: Apigenin is a naturally occurring compound found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. Many human trials of dietary interventions with apigenin-containing herbs and flavonoid mixture on oxidative stress markers, for instance, point to their antioxidant effects and health benefits in many diseases. Preclinical studies suggest that apigenin alone or its combination with chemotherapeutics has a strong anti-neoplastic effect and can induce ROS-mediated cytotoxicity at concentrations in the micromolar (μM) range, which may not be feasible with dietary interventions. Enhancing the in vivo pharmacokinetic properties of apigenin may be indispensable for its potential cancer-specific pro-oxidant therapy and may provide relevant information for clinical studies of apigenin either as a single agent or an adjuvant to chemotherapeutics.

Keywords:  antioxidant; apigenin; cancer; clinical translation; free radicals; pro-oxidant

DOI:  https://doi.org/10.1111/jfbc.14060
J Nanobiotechnology. 2022 Jan 06. 20(1): 20

Atom-precise fluorescent copper cluster for tumor microenvironment targeting and transient chemodynamic cancer therapy.

Zhenzhen Yang, Anli Yang, Wang Ma, Kai Ma, Ya-Kun Lv, Peng Peng, Shuang-Quan Zang, Bingjie Li.

   BACKGROUND: Reactive oxygen species (ROS) have been widely studied for cancer therapy. Nevertheless, instability and aspecific damages to cellular biomolecules limit the application effect. Recently, significant research efforts have been witnessed in the flourishing area of metal nanoclusters (NCs) with atomically precise structures for targeted release of ROS but few achieved success towards targeting tumor microenvironment.
RESULTS: In this work, we reported an atomically precise nanocluster Cu6(C4H3N2S)6 (Cu6NC), which could slowly break and generate ROS once encountered with acidic. The as-prepared Cu6NC demonstrated high biological safety and efficient chemodynamic anti-tumor properties. Moreover, Cu6NC enabled transient release of ROS and contained targeting behavior led by the tumor microenvironment. Both in vitro and in vivo experiments confirmed that Cu6NC demonstrated a low cytotoxicity for normal cells, while presented high cytotoxicity for tumor cells with a concentration-dependent manner.
CONCLUSIONS: This work not only reported a promising candidate for chemodynamic cancer therapy, but also paved the route to address clinical issues at the atomic level.

Keywords:  Cancer therapy; Nano clusters; ROS; Sustainable release; Targeting property

DOI:  https://doi.org/10.1186/s12951-021-01207-6
Front Pharmacol. 2021 ;12 735965

Ferroptosis-Inducing Nanomedicine for Cancer Therapy.

Yang Wang, Tianfu Liu, Xiang Li, Hui Sheng, Xiaowen Ma, Liang Hao.

  Ferroptosis, a new iron- and reactive oxygen species-dependent form of regulated cell death, has attracted much attention in the therapy of various types of tumors. With the development of nanomaterials, more and more evidence shows the potential of ferroptosis combined with nanomaterials for cancer therapy. Recently, there has been much effort to develop ferroptosis-inducing nanomedicine, specially combined with the conventional or emerging therapy. Therefore, it is necessary to outline the previous work on ferroptosis-inducing nanomedicine and clarify directions for improvement and application to cancer therapy in the future. In this review, we will comprehensively focus on the strategies of cancer therapy based on ferroptosis-inducing nanomedicine currently, elaborate on the design ideas of synthesis, analyze the advantages and limitations, and finally look forward to the future perspective on the emerging field.

Keywords:  ROS; cancer therapy; combination strategies; ferroptosis; nanomedicine

DOI:  https://doi.org/10.3389/fphar.2021.735965
Free Radic Biol Med. 2021 Dec 29. pii: S0891-5849(21)01175-8. [Epub ahead of print]

Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling.

Yue Zhang, Shibo Sun, Weiping Xu, Rui Yang, Yijia Yang, Jianli Guo, Kun Ma, Jianqiang Xu.

  Shikonin, a naturally occurring naphthoquinone with potent anti-tumor activity, has been reported to induce cancer cell death via targeting selenoenzyme thioredoxin reductase 1 (TrxR1; TXNRD1). However, the interaction between shikonin and TrxR1 remains unclear, and the roles of the cellular antioxidant system in shikonin induced cell death are obscure. Here, we found that shikonin modified the Sec498 residue of TrxR1 to fully inhibit its antioxidant activity, however, the shikonin-modified TrxR1 still remained intrinsic NADPH oxidase activity, which promotes superoxide anions production. Besides, TrxR1 efficiently reduced shikonin in both selenocysteine dependent and selenocysteine independent manners, the oxygen-coupled redox cycling of shikonin also generates excessive superoxide anions. The inhibitory effects and the redox cycling of shikonin towards TrxR1 caused cancer cell ROS-dependent necroptosis. Interestingly, as we evaluated, some cancer cell lines were insensitive to shikonin, especially kelch-like ECH associated protein 1 (KEAP1)-mutant non-small cell lung cancer (NSCLC) cells, which harbor constitutive activation of the nuclear factor-erythroid 2-related factor 2 (NRF2). NADPH bankrupt caused by glucose starvation or glucose limitation (inhibiting glucose transporter 1 by BAY-876) could efficiently overcome the resistance of KEAP1-mutant NSCLC cells to shikonin. Glucose-6-phosphate dehydrogenase (G6PD), was known as a rate-limiting enzyme in the pentose phosphate pathway, however, the pharmacological inhibition of G6PD by 6-aminonicotinamide (6-AN), enhanced the shikonin-induced cytotoxicity but has no selectivity on KEAP1-mutant NSCLC cells. This study will be helpful in applying shikonin for potential chemotherapy, and in combinational treatment of KEAP1-mutant NSCLC.

Keywords:  Glucose starvation; KEAP1 mutation; NSCLC; Reactive oxygen species; Shikonin; Thioredoxin reductase

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.314
Turk J Pharm Sci. 2021 Dec 31. 18(6): 781-789

Investigation of the Genotoxic, Cytotoxic, Apoptotic, and Oxidant Effects of Olive Leaf Extracts on Liver Cancer Cell Lines.

Muhammed Yunus Bektay, Eray Metin Güler, Mustafa Gökçe, Mustafa Volkan Kızıltaş.

   Objectives: Hepatocellular carcinoma (HCC) is the seventh most common cancer and the third leading cause of tumor-related deaths worldwide. Mechanisms underlying tumor onset, progression, and metastasis in the case of HCC have not been adequately studied. In this study, we aimed to investigate the genotoxic, cytotoxic, apoptotic and oxidant effects of olive leaf extract (OLE) on HCC cells.
Materials and Methods: H4IIE Rattus norvegicus hepatoma cells and Rattus norvegicus healthy liver clone-9 cells were treated with the increasing concentrations of OLEs (250-2000 ppm) in ethanol, acetone, dichloromethane, and methanol. ATP cell viability, intracellular reactive oxygen species generation levels, double staining test with acridine orange/ethidium bromide, comet assay, levels of interleukin 1-beta (IL-1β), IL-6, and tumor necrosis factor alpha were measured. Significance was determined using ANOVA test.
Results: Apoptotic, genotoxic, cytotoxic, and oxidative effects of OLEs increased with the increasing concentrations as compared to controls in H4IIE cells (p<0.001).
Conclusion: This is the first study to show a significant and selective cytotoxic activity of OLEs in the selected H4IIE cancer cell lines. OLEs could selectively increase the apoptotic damage and show anti-proliferative and pro-apoptotic properties against the H4IIE cells. They could be recommended as potential nutraceuticals in the prevention of cancer.

Keywords:  Olive leaf; apoptosis; genotoxicity; hepatocellular carcinoma; oleuropein; oxidative stress

DOI:  https://doi.org/10.4274/tjps.galenos.2021.03271
ACS Biomater Sci Eng. 2022 Jan 06.

ROS-Mediated Anti-Angiogenic Activity of Cerium Oxide Nanoparticles in Melanoma Cells.

Joel M Yong, Lu Fu, Fengying Tang, Peimin Yu, Rhiannon P Kuchel, John M Whitelock, Megan S Lord.

  Angiogenesis plays a key role in cancer progression, including transition to the metastatic phase via reactive oxygen species (ROS)-dependent pathways, among others. Antivascular endothelial growth factor (VEGF) antibodies have been trialed as an anti-angiogenic therapy for cancer but are associated with high cost, limited efficacy, and side effects. Cerium oxide nanoparticles (nanoceria) are promising nanomaterials for biomedical applications due to their ability to modulate intracellular ROS. Nanoceria can be produced by a range of synthesis methods, with chemical precipitation as the most widely explored. It has been reported that chemical precipitation can fine-tune primary particle size where a limited number of synthesis parameters were varied. Here, we explore the effect of temperature, precipitating agent concentration and rate of addition, stirring rate, and surfactant concentration on nanoceria primary particle size using a fractional factorial experimental design approach. We establish a robust synthesis method for faceted nanoceria with primary particle diameters of 5-6 nm. The nanoceria are not cytotoxic to a human melanoma cell line (Mel1007) at doses up to 400 μg/mL and are dose-dependently internalized by the cells. The intracellular ROS level for some cells that internalized the nanoceria is reduced, which correlates with a dose-dependent reduction in angiogenic gene expression including VEGF. These findings contribute to our knowledge of the anti-angiogenic effects of nanoceria and help to develop our understanding of potentially new anti-angiogenic agents for combination cancer therapies.

Keywords:  angiogenesis; cerium oxide; melanoma; nanoparticle; redox

DOI:  https://doi.org/10.1021/acsbiomaterials.1c01268
ACS Appl Mater Interfaces. 2022 Jan 04.

Ultrasound-Enhanced Reactive Oxygen Species Responsive Charge-Reversal Polymeric Nanocarriers for Efficient Pancreatic Cancer Gene Delivery.

Cong Zhang, Jifan Chen, Yue Song, Jiali Luo, Peile Jin, Xue Wang, Lei Xin, Fuqiang Qiu, Jianting Yao, Guowei Wang, Pintong Huang.

  Inefficient intracellular gene release and transfection limit nonviral gene delivery applications in cancer therapy. Reactive oxygen species (ROS) responsive nonviral gene delivery is the most widely explored strategy for such applications, yet the development of fast and safe ROS responsive nanocarriers proves to be a challenge because of the intracellular chemical equilibrium of high ROS and glutathione levels. Here, we report an ultrasound-enhanced ROS responsive charge-reversal polymeric nanocarrier (BTIL) for fast and efficient pancreatic cancer gene delivery. The BTIL is composed of B-PDEAEA/DNA polyplex-based cores and IR780-loaded liposome coatings. The IR780 is able to produce an excess of ROS under low intensity ultrasound irradiation, thus disequilibrating the chemical equilibrium of ROS and glutathione, and promoting the ROS-responsive positive-to-negative charge-reversal of the B-PDEAEA polymer. This charge conversion results in fast polyplex dissociation and intracellular gene release, inducing efficient gene transfection and cancer cell apoptosis. Moreover, following the intravenous administration, BTIL maintains a stable and long circulation in the bloodstream, achieves orthotopic pancreatic ductal adenocarcinoma distribution, and exhibits potent antitumor activity with negligible side effects. Our results reveal the proposed strategy to be both promising and universal for the development of fast and safe ROS responsive nonviral gene delivery in cancer therapy.

Keywords:  charge-reversal; nonviral gene delivery; pancreatic cancer; reactive oxygen species responsive; ultrasound

DOI:  https://doi.org/10.1021/acsami.1c20030
Crit Rev Food Sci Nutr. 2022 Jan 07. 1-26

Regulation of reactive oxygen species by phytochemicals for the management of cancer and diabetes.

Heui Min Lim, See-Hyoung Park.

  Cancer and diabetes mellitus are served as typical life-threatening diseases with common risk factors. Developing therapeutic measures in cancers and diabetes have aroused attention for a long time. However, the problems with conventional treatments are in challenge, including side effects, economic burdens, and patient compliance. It is essential to secure safe and efficient therapeutic methods to overcome these issues. As an alternative method, antioxidant and pro-oxidant properties of phytochemicals from edible plants have come to the fore. Phytochemicals are naturally occurring compounds, considered promising agent applicable in treatment of various diseases with beneficial effects. Either antioxidative or pro-oxidative activity of various phytochemicals were found to contribute to regulation of cell proliferation, differentiation, cell cycle arrest, and apoptosis, which can exert preventive and therapeutic effects against cancer and diabetes. In this article, the antioxidant or pro-oxidant effects and underlying mechanisms of flavonoids, alkaloids, and saponins in cancer or diabetic models demonstrated by the recent studies are summarized.

Keywords:  Cancers; antioxidant; diabetes; phytochemicals; pro-oxidant; reactive oxygen species

DOI:  https://doi.org/10.1080/10408398.2022.2025574
JACS Au. 2021 Dec 27. 1(12): 2328-2338

Hybrid Carbon Dot Assembly as a Reactive Oxygen Species Nanogenerator for Ultrasound-Assisted Tumor Ablation.

Deblin Jana, Dongdong Wang, Praveenbalaji Rajendran, Anivind Kaur Bindra, Yi Guo, Jiawei Liu, Manojit Pramanik, Yanli Zhao.

The efficacy of reactive oxygen species (ROS)-based therapy is substantially constrained by the limited ROS generation, stern activation conditions, and lack of a straightforward reaction paradigm. Carbon dots (CDs) have been highly sought after for therapeutic applications for their biocompatibility and intrinsic fluorescence imaging capabilities, making them suitable for ROS generation. Herein, we synthesized a CD-based ultrasmall hybrid nanostructure possessing active sites of Mo, Cu, and IR-780 dye. After cooperative self-assembly with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol), the obtained assembly (CMIR-CDa) exhibits near-infrared fluorescence imaging and photoacoustic tomography. Interestingly, CMIR-CDa can generate singlet oxygen (1O2), hydroxyl radical (·OH), and superoxide radical anion (O2 • -) upon ultrasound stimulus owing to its sonosensitizing and enzyme-mimicking properties, showing an enhanced efficacy for tumor ablation in vivo. The collective in vitro and in vivo results indicate that CMIR-CDa has a high potency as an ROS nanogenerator under US irradiation, even at a low concentration. The present study offers an approach for engineering hybrid CDs in a bioinspired way for intratumoral ROS augmentation in response to deep tissue penetrable external stimuli.

DOI: https://doi.org/10.1021/jacsau.1c00422
J Hazard Mater. 2021 Dec 28. pii: S0304-3894(21)03130-7. [Epub ahead of print]427 128160

Anticancer potential and through study of the cytotoxicity mechanism of ionic liquids that are based on the trifluoromethanesulfonate and bis(trifluoromethylsulfonyl)imide anions.

Micha Kuczak, Małgorzata Musiał, Katarzyna Malarz, Patryk Rurka, Edward Zorębski, Robert Musioł, Marzena Dzida, Anna Mrozek-Wilczkiewicz.

  Ionic liquids (ILs) are known for their unique physicochemical properties. However, despite the great number of published papers, still little attention has been paid to their biological activity. Anticancer potential and the molecular mechanisms underlying the toxicity of these compounds are especially interesting and still unexplored. In the current work, a broad analysis of the cytotoxicity towards colon and breast cancers as well as glioblastoma of the ILs with pyridinium, piperidinium, pyrrolidinium, and imidazolium cations and trifluoromethanesulfonate or bis(trifluoromethylsulfonyl)imide anions indicated previously as the most toxic for normal human dermal fibroblasts were presented. In the case of MCF-7 cells, the activity of 1-decyl-3-methylimidazolium trifluoromethanesulfonate was more than twice as high as cisplatin. It was found that the inhibition of the cell cycle of colon cancer and glioblastoma cells occurs in different phases. More importantly, the different types of cell death were detected for both selected ILs, namely 1-hexyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide and 1-hexyl-3-methylimidazolium trifluoromethane-sulfonate, on colon cancer and glioblastoma, respectively, apoptosis and autophagy, confirmed at the gene and protein levels. Additionally, kinetic studies of the reactive oxygen species indicated that the tested ILs disturbed the cellular redox homeostasis.

Keywords:  Apoptosis; Autophagy; Cell cycle inhibition; Cytotoxicity; Ionic liquids; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.jhazmat.2021.128160
Int J Environ Health Res. 2022 Jan 02. 1-15

Malignant growth of arsenic-transformed cells depends on activated Akt induced by reactive oxygen species.

Qun Lou, Fuxun Chen, Bingyang Li, Meichen Zhang, Fanshuo Yin, Xiaona Liu, Zaihong Zhang, Xin Zhang, Chenlu Fan, Yanhui Gao, Yanmei Yang.

  Arsenic is an identified carcinogen for humans.In this study, chronic exposure of human hepatocyte L-02 to low-doses of inorganic arsenic caused cell malignant proliferation. Meanwhile, compared with normal L-02 cells, arsenic-transformed malignant cells, L-02-As displayed more ROS and significantly higher Cyclin D1 expression as well as aerobic glycolysis. Moreover, Akt activation is followed by the upregulation of Cyclin D1 and HK2 expression in L-02-As cells, since inhibition of Akt activity by Ly294002 attenuated the colony formation in soft agar and decreased the levels of Cyclin D1 and HK2. In addition, scavenging of ROS by NAC resulted in a decreased expression of phospho-Akt, HK2 and Cyclin D1, and attenuates the ability of anchorage-independent growth ofL-02-As cells, suggested that ROS mediated the Akt activation in L-02-As cells. In summary, our results demonstrated that ROS contributes to the malignant phenotype of arsenic-transformed human hepatocyte L-02-As via the activation of Akt pathway.

Keywords:  Akt; Arsenic exposure; Cyclin D1; GSK-3β; ROS; glycolysis; malignant phenotype

DOI:  https://doi.org/10.1080/09603123.2021.2023113
Toxicol Appl Pharmacol. 2021 Dec 31. pii: S0041-008X(21)00461-0. [Epub ahead of print] 115857

A novel halogenated adenosine analog 5'-BrDA displays potent toxicity against colon cancer cells in vivo and in vitro.

Long Ma, Yingying Lu, Yaqin Li, Zhizhen Yang, Yu Mao, Yi Wang, Shuli Man.

  Adenosine, as a naturally occurring nucleoside, plays an important role in human health maintenance. In recent years, many studies have shown that adenosine has the effect of cancer inhibition, and some of its analogs have been successfully marketed as anticancer drugs. This report mainly describes the anti-colon cancer activities and mechanism of a novel halogenated adenosine analog named 5'-bromodeoxyadenosine (5'-BrDA). As a result, 5'-BrDA concentration-dependently inhibited colon cancer cells proliferation, induced autophagy without disruption of lysosomal stability, and promoted autophagy-independently cellular mitochondrial apoptosis by increasing the accumulation of reactive oxygen species. Furthermore, 5'-BrDA inhibited the tumor growth of colon cancer in CT26 inbred mice without affecting the body weight in vivo. Collectively, the above-mentioned mechanisms contributed to the anticancer activity of 5'-BrDA. It is rare to discover novel anticancer adenosine analogs during the past couple of decades. We believe that our work will enrich the understanding of adenosine analogs, also, pave the way for adenosine analogs product based anticancer drug development.

Keywords:  Anti-colon cancer; Apoptosis; Autophagy; Halogenated adenosine analogue; ROS overproduction

DOI:  https://doi.org/10.1016/j.taap.2021.115857
Toxicol Appl Pharmacol. 2021 Dec 29. pii: S0041-008X(21)00456-7. [Epub ahead of print]435 115852

Role of ferroptosis in promoting cardiotoxicity induced by Imatinib Mesylate via down-regulating Nrf2 pathways in vitro and in vivo.

Chengzhu Song, Dongning Li, Jie Zhang, Xiaoyan Zhao.

  Imatinib Mesylate (IMA) has been widely used to treat with chronic myeloid leukemia (CML). However, cardiotoxicity associated with IMA is included among the therapeutic strategies. The present study was aimed to discover whether ferroptosis, a programmed iron-dependent cell death, is involved in IMA-induced cardiotoxicity. In vivo, mouse model was established after treated with 25 mg/kg, 50 mg/kg and 100 mg/kg IMA. Serum CK, LDH, AST activities were determined. Cardiac tissues were examined by H&E and Oil Red O staining. MDA was measured to assess production of lipid peroxide. Tissue iron and GSH content were measured. In vitro, cell viability, mitochondria membrane potential, generation of reactive oxygen species (ROS) and cellular iron levels were performed to explore the mechanism of IMA. The in vivo results revealed that IMA treatment significantly increased serum CK, LDH and AST. H&E staining showed that IMA caused cardiac structural injuries. The dose-dependent decrease of GSH and increase of tissue iron and MDA were observed in IMA-treated groups. Oil Red O staining suggested obvious cardiac lipid accumulation after treated with IMA. In H9c2 cardiomyocytes, IMA significantly inhibited cell proliferation in a dose-dependent manner. Mitochondria membrane potential assay showed that IMA destroyed the mitochondrial function. Additionally, IMA increased the cellular ROS and iron levels. Furthermore, IMA down-regulated the expression of Nrf2 and up-regulated the expression of P53 and TfR. These results provided compelling evidence that ferroptosis participates in IMA-induced cardiotoxicity. Ferroptosis could be regarded as a target to protect against cardiotoxicity in IMA-exposed patients.

Keywords:  Cardiotoxicity; Ferroptosis; Imatinib Mesylate; Mechanism; Nrf2 Pathways

DOI:  https://doi.org/10.1016/j.taap.2021.115852
ChemMedChem. 2022 Jan 04.

Biguanide MC001, a dual inhibitor of OXPHOS and glycolysis, shows enhanced anti-tumor activity without increasing lactate production.

Jiamiao Fu, Siyu Liu, Minqiang Hu, Ximing Liao, Xiaoquan Wang, Zhengshuang Xu, Qinkai Li, Junmin Quan.

  Metformin and other biguanides represent a new class of inhibitors of mitochondrial complex I that show promising anti-tumor effects, but stronger inhibition of mitochondrial complex I is generally associated with upregulation of glycolysis and higher risk of lactic acidosis. Here we reported a novel biguanide derivative N-cystaminylbiguanide (MC001) that inhibited mitochondrial complex I with higher potency while induced similar lactate production compared with metformin. Furthermore, MC001 was found to efficiently inhibit a panel of colorectal cancer (CRC) cells in vitro, and suppress tumor growth in HCT116 xenograft nude mice model while did not enhance lactate production compared with metformin, exhibiting superior safety profile to other potent biguanides such as phenformin. Mechanistically, MC001 efficiently inhibited mitochondrial complex I, activated AMPK and repressed mTOR, leading to cell cycle arrest and apoptosis. Notably, MC001 inhibited both oxidative phosphorylation (OXPHOS) and glycolysis. We thus propose that MC001 warrants further investigation in cancer treatment.

Keywords:  Biguanide; Glycolysis; Lactate production; Mitochondrial complex I; Oxidative phosphorylation

DOI:  https://doi.org/10.1002/cmdc.202100674
Adv Sci (Weinh). 2022 Jan 05. e2101935

Lymph-Directed Self-Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer.

Taejeong Kim, Jeeyeon Suh, Jihoon Kim, Won Jong Kim.

  There has been a significant clinical demand for lymph-directed anti-metastatic therapy as tumor-draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor-related deaths. Despite the high potential of nitric oxide (NO) in anti-cancer therapy owing to its biocompatibility and tumor cell-specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox-triggered self-immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin-prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on-demand NO delivery systems for anti-metastatic therapy and other treatments.

Keywords:  lymph-directed drug delivery; metastatic cancer therapy; nitric oxide; prodrug; redox chemistry

DOI:  https://doi.org/10.1002/advs.202101935