bims-rehoca 2021-11-14 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021‒11‒14
twenty-two papers selected by
Vittoria Raimondi
Veneto Institute of Oncology

Targeting the Redox Imbalance in Mitochondria: A revolutionary mode for cancer therapy.
Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.
ROS-Activated homodimeric podophyllotoxin nanomedicine with self-accelerating drug release for efficient cancer eradication.
Sanguinarine impairs lysosomal function and induces ROS-dependent mitophagy and apoptosis in human hepatocellular carcinoma cells.
Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy.
Inhibition of Proliferation in Ovarian Cancer Cell Line (PA-1) by the Action of Green Compound "Betanin".
The new andrographolide derivative AGS-30 induces apoptosis in human colon cancer cells by activating a ROS-dependent JNK signalling pathway.
Antitumor Effects of Selenium.
Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax.
Patient-Derived Human Basal and Cutaneous Squamous Cell Carcinoma Tissues Display Apoptosis and Immunomodulation following Gas Plasma Exposure with a Certified Argon Jet.
Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress.
Human Telomerase Reverse Transcriptase as a Therapeutic Target of Dihydroartemisinin for Esophageal Squamous Cancer.
Broussochalcone A Induces Apoptosis in Human Renal Cancer Cells via ROS Level Elevation and Activation of FOXO3 Signaling Pathway.
Benzyl Isothiocyanate, a Vegetable-Derived Compound, Induces Apoptosis via ROS Accumulation and DNA Damage in Canine Lymphoma and Leukemia Cells.
Aberrant ROS Mediate Cell Cycle and Motility in Colorectal Cancer Cells Through an Oncogenic CXCL14 Signaling Pathway.
DOX-loaded silver nanotriangles and photothermal therapy exert a synergistic antibreast cancer effect via ROS/ERK1/2 signaling pathway.
Oxidative Stress Induced Cell Cycle Arrest: Potential Role of PRX-2 and GSTP-1 as Therapeutic Targets in Hepatocellular Carcinoma.
ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling.
The role of ferroptosis in lung cancer.
15d-PGJ2 Promotes ROS-Dependent Activation of MAPK-Induced Early Apoptosis in Osteosarcoma Cell In Vitro and in an Ex Ovo CAM Assay.
Highly Efficient Ir(III)-coumarin Photo-redox Catalyst for Synergetic Multi-mode Cancer Photo-therapy.
Selective in vitro anticancer effect of blueberry extract (Vaccinium virgatum) against C6 rat glioma: exploring their redox status.

Mitochondrion. 2021 Nov 07. pii: S1567-7249(21)00152-5. [Epub ahead of print]

Targeting the Redox Imbalance in Mitochondria: A revolutionary mode for cancer therapy.

Shalini Mani, Geeta Swargiary, Stephen J Ralph.

  Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.

Keywords:  Mitochondria; cancer; oxidative stress; pro-oxidants; redox imbalance

DOI:  https://doi.org/10.1016/j.mito.2021.11.002
Cancers (Basel). 2021 Oct 31. pii: 5484. [Epub ahead of print]13(21):

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.

Serena Castelli, Pamela De Falco, Fabio Ciccarone, Enrico Desideri, Maria Rosa Ciriolo.

  Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold. In those conditions, ROS can act as second messengers, favouring proliferation and survival. Herein, we highlight the different responses that tumor cells adopt when lipid catabolism is augmented, taking into account the different ROS fates. Many papers have demonstrated that the pro- or anti-tumoral roles of endogenous FA usage are hugely dependent on the tumor type, and on the capacity of cancer cells to maintain redox homeostasis. In light of this, clinical studies have taken advantage of the boosting of lipid catabolism to increase the efficacy of tumor therapy, whereas, in other contexts, antioxidant compounds are useful to reduce the pro-survival effects of ROS deriving from FAO.

Keywords:  fatty acid oxidation; lipid catabolism; mitochondrial metabolism; reactive oxygen species

DOI:  https://doi.org/10.3390/cancers13215484
Drug Deliv. 2021 Dec;28(1): 2361-2372

ROS-Activated homodimeric podophyllotoxin nanomedicine with self-accelerating drug release for efficient cancer eradication.

Bingfeng Liang, Dangxia Zhou.

  Although podophyllotoxin (POD) demonstrates high efficiency to inhibit various cancers, its clinic application is limited to poor bioavailability. Nanoparticles derived from homodimeric prodrugs with high drug loading potential are emerging as promising nanomedicines. However, complete intracellular drug release remains a major hindrance to the use of homodimeric prodrugs-based nanomedicine. We sought to develop a reactive oxygen species (ROS) responsive POD dimeric prodrug by incorporating vitamin K3 (VK3) and Pluronic F127 to synthesize a spheroid nanoparticle (PTV-NPs). PTV-NPs with high POD content could release drugs under the ROS enrichment microenvironment in cancer cells. The released VK3 could produce abundant ROS selectively in tumor cells catalyzed by the overexpressed NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme. In turn, the resultant high ROS concentration promoted the conversion of POD dimeric prodrug to POD monomer, thereby achieving the selective killing of cancer cells with weak system toxicity. In vitro and in vivo studies consistently confirmed that PTV-NPs exhibit high drug loading potential and upstanding bioavailability. They are also effectively internalized by tumor cells, induce abundant intracellular ROS generation, and have high tumor-specific cytotoxicity. This ROS-responsive dimeric prodrug nanoplatform characterized by selective self-amplification drug release may hold promise in the field of antitumor drug delivery.

Keywords:  Dimeric prodrug; ROS generation; high drug loading; tumor-specific drug release; vitamin K3

DOI:  https://doi.org/10.1080/10717544.2021.1995076
Arch Pharm Res. 2021 Nov 09.

Sanguinarine impairs lysosomal function and induces ROS-dependent mitophagy and apoptosis in human hepatocellular carcinoma cells.

Jingjing Wang, Qi Su, Qing Wu, Kun Chen, Asmat Ullah, Mohsin Ahmad Ghauri, Yanmin Zhang.

  Hepatocellular carcinoma (HCC) is one of the most common tumor types globally. Despite the progress made in surgical procedures and therapeutic options, HCC remains a considerable cause of cancer-related mortality. In this study, we investigated the antitumor effects of sanguinarine (Sang) on HCC and its potential mechanisms. Our findings showed that Sang impairs the acidic environment of lysosomes by inhibiting cathepsin D maturation. In addition, Sang inhibited the formation of autolysosomes in RFP-GFP-LC3 transfected cells, subsequently suppressing late mitophagy. Sang also induced reactive oxygen species (ROS)-dependent autophagy and apoptosis in HCC cells, which was significantly attenuated following treatment with a ROS scavenger. Further investigation using autophagy inhibitors revealed that sanguinarine-induced mitochondrial dysfunction and mitophagy led to mitochondrial apoptosis in HCC cells. Immunohistochemical staining of sanguinarine-treated xenograft samples revealed that it initiated and blocked autophagy. In summary, our findings suggest that in HCC cells, Sang impairs lysosomal function and induces ROS-dependent mitophagy and apoptosis.

Keywords:  Apoptosis; Hepatocellular carcinoma; Lysosomal function; Mitophagy; Reactive oxygen species; Sanguinarine

DOI:  https://doi.org/10.1007/s12272-021-01356-0
Colloids Surf B Biointerfaces. 2021 Oct 30. pii: S0927-7765(21)00633-0. [Epub ahead of print]209(Pt 1): 112189

Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy.

Quan Truong Hoang, Miyeon Kim, Byoung Choul Kim, Chang Yeon Lee, Min Suk Shim.

  Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN-222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEG-PCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy.

Keywords:  Combination cancer therapy; Metal organic frameworks (MOFs); Piperlongumine; Reactive oxygen species; Sonodynamic therapy

DOI:  https://doi.org/10.1016/j.colsurfb.2021.112189
Appl Biochem Biotechnol. 2021 Nov 11.

Inhibition of Proliferation in Ovarian Cancer Cell Line (PA-1) by the Action of Green Compound "Betanin".

Rakshanaa R, Mohiraa Shafreen, Nitin Kumar.

  Ovarian carcinoma has a cure rate of 30% which makes it deadlier than any other disease. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Chemoprevention of cancer through application of natural compounds is the need of present generation as other methods are rigorous and have many side effects. Betanin, a compound from Beta vulgaris extract is used in present study to check its potential for inhibition of (PA-1) cancer cell proliferation. Determination of IC50 values through MTT assay was carried out, in addition measurement of mitochondrial membrane potential (MMP), effect of reactive oxygen species (ROS) generation, and induction of apoptosis in ovarian cancer cells through betanin was also observed. Results have shown betanin as a potential candidate for inhibition of ovarian cancer cell proliferation and it can be taken up as a serious compound for further studies for its application in cancer cure.

Keywords:  Apoptosis; Betanin; MTT assay; Mitochondrial membrane potential; Ovarian cancer; Reactive oxygen species

DOI:  https://doi.org/10.1007/s12010-021-03744-0
Phytomedicine. 2021 Oct 24. pii: S0944-7113(21)00363-9. [Epub ahead of print]94 153824

The new andrographolide derivative AGS-30 induces apoptosis in human colon cancer cells by activating a ROS-dependent JNK signalling pathway.

Zhuyun Liu, Xiaoping Wu, Kun Dai, Renkai Li, Jinming Zhang, Dekuan Sheng, Simon Ming-Yuen Lee, George Pak-Heng Leung, Guo-Chun Zhou, Jingjing Li.

  BACKGROUND: The anti-cancer activity of andrographolide (Andro) has been extensively demonstrated in recent years. It is supposed that modifying the chemical structure of Andro can improve its efficacy and reduce its toxicity.PURPOSE: In this study, the anti-cancer effect of a 14β-(2'-chlorophenoxy) derivative of andrographolide known as AGS-30 was investigated, and its underlying mechanisms were also explored.
STUDY DESIGN/METHODS: Different cancer cells were used to evaluate and compare the in vitro anti-cancer effects of Andro and AGS-30. Human colon cancer cells HT-29 and HCT-116 were used to study the underlying anti-cancer mechanisms of AGS-30. HT-29 cells xenografted in nude mouse model was used to compare the in vivo anti-tumour efficacies of Andro and AGS-30.
RESULT: In vitro studies showed that AGS-30 possessed an anti-cancer effect by inhibiting the viability, colony formation and migration of cancer cells. It significantly induced the generation of reactive oxygen species (ROS), caused the loss of mitochondrial membrane potential and triggered the apoptosis in colon cancer cells. These effects of AGS-30 were more potent than those of Andro. In addition, the expression levels of proteins associated with apoptosis, including phospho-JNK1/2 as well as cleaved caspase 9, caspase 3, and poly(ADP ribose) polymerase, were elevated in AGS-30-treated colon cancer cells. Moreover, these elevated levels of the proteins were inhibited by the antioxidant N-acetylcysteine and the JNK inhibitor SP600125, suggesting the involvement of ROS/JNK-dependent mechanisms in AGS-30-induced apoptosis. The in vitro anti-cancer effect could be reproduced in an HT-29 colon cancer cell xenografted nude mouse model.
CONCLUSION: The anti-cancer effect of AGS-30 is stronger than that of Andro. AGS-30 induces apoptosis of colon cancer cells through ROS/JNK-dependent pathway. Our findings may provide insights for the future development of derivatives of Andro as novel chemotherapeutic agents.

Keywords:  Andrographolide derivative; Apoptosis; Colon cancer; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.phymed.2021.153824
Int J Mol Sci. 2021 Oct 31. pii: 11844. [Epub ahead of print]22(21):

Antitumor Effects of Selenium.

Seung Jo Kim, Min Chul Choi, Jong Min Park, An Sik Chung.

  Functions of selenium are diverse as antioxidant, anti-inflammation, increased immunity, reduced cancer incidence, blocking tumor invasion and metastasis, and further clinical application as treatment with radiation and chemotherapy. These functions of selenium are mostly related to oxidation and reduction mechanisms of selenium metabolites. Hydrogen selenide from selenite, and methylselenol (MSeH) from Se-methylselenocyteine (MSeC) and methylseleninicacid (MSeA) are the most reactive metabolites produced reactive oxygen species (ROS); furthermore, these metabolites may involve in oxidizing sulfhydryl groups, including glutathione. Selenite also reacted with glutathione and produces hydrogen selenide via selenodiglutathione (SeDG), which induces cytotoxicity as cell apoptosis, ROS production, DNA damage, and adenosine-methionine methylation in the cellular nucleus. However, a more pronounced effect was shown in the subsequent treatment of sodium selenite with chemotherapy and radiation therapy. High doses of sodium selenite were effective to increase radiation therapy and chemotherapy, and further to reduce radiation side effects and drug resistance. In our study, advanced cancer patients can tolerate until 5000 μg of sodium selenite in combination with radiation and chemotherapy since the half-life of sodium selenite may be relatively short, and, further, selenium may accumulates more in cancer cells than that of normal cells, which may be toxic to the cancer cells. Further clinical studies of high amount sodium selenite are required to treat advanced cancer patients.

Keywords:  ROS; apoptosis; metastasis; selenium compounds; treatment of advanced cancer patients

DOI:  https://doi.org/10.3390/ijms222111844
Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab148

Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax.

Masahiro Yamamoto, Tomomi Sanomachi, Shuhei Suzuki, Keita Togashi, Asuka Sugai, Shizuka Seino, Atsushi Sato, Masashi Okada, Chifumi Kitanaka.

  Background: Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells.Methods: We examined the radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms.
Results: Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells.
Conclusion: These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.

Keywords:  gemcitabine; malignant meningioma; radiation; senescence; senolytics

DOI:  https://doi.org/10.1093/noajnl/vdab148
Int J Mol Sci. 2021 Oct 23. pii: 11446. [Epub ahead of print]22(21):

Patient-Derived Human Basal and Cutaneous Squamous Cell Carcinoma Tissues Display Apoptosis and Immunomodulation following Gas Plasma Exposure with a Certified Argon Jet.

Fariba Saadati, Juliane Moritz, Julia Berner, Eric Freund, Lea Miebach, Iris Helfrich, Ingo Stoffels, Steffen Emmert, Sander Bekeschus.

  Reactive oxygen species (ROS) have been subject of increasing interest in the pathophysiology and therapy of cancers in recent years. In skin cancer, ROS are involved in UV-induced tumorigenesis and its targeted treatment via, e.g., photodynamic therapy. Another recent technology for topical ROS generation is cold physical plasma, a partially ionized gas expelling dozens of reactive species onto its treatment target. Gas plasma technology is accredited for its wound-healing abilities in Europe, and current clinical evidence suggests that it may have beneficial effects against actinic keratosis. Since the concept of hormesis dictates that low ROS levels perform signaling functions, while high ROS levels cause damage, we investigated herein the antitumor activity of gas plasma in non-melanoma skin cancer. In vitro, gas plasma exposure diminished the metabolic activity, preferentially in squamous cell carcinoma cell (SCC) lines compared to non-malignant HaCaT cells. In patient-derived basal cell carcinoma (BCC) and SCC samples treated with gas plasma ex vivo, increased apoptosis was found in both cancer types. Moreover, the immunomodulatory actions of gas plasma treatment were found affecting, e.g., the expression of CD86 and the number of regulatory T-cells. The supernatants of these ex vivo cultured tumors were quantitatively screened for cytokines, chemokines, and growth factors, identifying CCL5 and GM-CSF, molecules associated with skin cancer metastasis, to be markedly decreased. These findings suggest gas plasma treatment to be an interesting future technology for non-melanoma skin cancer topical therapy.

Keywords:  ROS; chemokines; cold physical plasma; cytokines; reactive oxygen species; skin cancer

DOI:  https://doi.org/10.3390/ijms222111446
Oncogene. 2021 Nov 12.

Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress.

Xiaohe Hao, Wenqing Bu, Guosheng Lv, Limei Xu, Dong Hou, Jing Wang, Xiaojie Liu, Tingting Yang, Xiyu Zhang, Qiao Liu, Yaoqin Gong, Changshun Shao.

Reactive oxygen species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in cancer cells treated with anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. CHK1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in cancer therapy.

DOI: https://doi.org/10.1038/s41388-021-02105-9
Front Pharmacol. 2021 ;12 769787

Human Telomerase Reverse Transcriptase as a Therapeutic Target of Dihydroartemisinin for Esophageal Squamous Cancer.

Qingrong Li, Qiang Ma, Lei Xu, Chuanli Gao, Lihua Yao, Jilin Wen, Miyuan Yang, Jibing Cheng, Xi Zhou, Jiang Zou, Xiaowu Zhong, Xiaolan Guo.

  Objective: To elucidate the oncogenic role of human telomerase reverse transcriptase (hTERT) in esophageal squamous cancer and unravel the therapeutic role and molecular mechanism of dihydroartemisinin (DHA) by targeting hTERT. Methods: The expression of hTERT in esophageal squamous cancer and the patients prognosis were analyzed by bioinformatic analysis from TCGA database, and further validated with esophageal squamous cancer tissues in our cohort. The Cell Counting Kit-8 (CCK8) and colony formation assay were used to evaluate the proliferation of esophageal squamous cancer cell lines (Eca109, KYSE150, and TE1) after hTERT overexpression or treated with indicated concentrations of DHA. Transwell migration assay and scratch assay were employed to determine the migration abilities of cancer cells. Fluorescence microscopy and flow cytometry were conducted to measure the intracellular reactive oxygen species (ROS) levels in cancer cells after treated with DHA. Moreover, RT-PCR and Western blot were performed to test the alteration of associated genes on mRNA and protein level in DHA treated esophageal squamous cancer cell lines, respectively. Furthermore, tumor-bearing nude mice were employed to evaluate the anticancer effect of DHA in vivo. Results: We found that hTERT was significantly upregulated in esophageal squamous cancer both from TCGA database and our cohort also. Overexpression of hTERT evidently promoted the proliferation and migration of esophageal squamous cancer cells in vitro. Moreover, DHA could significantly inhibit the proliferation and migration of esophageal cancer cell lines Eca109, KYSE150, and TE1 in vitro, and significantly down-regulate the expression of hTERT on both mRNA and protein level in a time- and dose-dependent manner as well. Further studies showed that DHA could induce intracellular ROS production in esophageal cancer cells and down-regulate SP1 expression, a transcription factor that bound to the promoter region of hTERT gene. Moreover, overexpression of SP1 evidently promoted the proliferation and migration of Eca109 and TE1 cells. Intriguingly, rescue experiments showed that inhibiting ROS by NAC alleviated the downregulation of SP1 and hTERT in cells treated with DHA. Furthermore, overexpression of SP1 or hTERT could attenuate the inhibition effect of DHA on the proliferation and migration of Eca109 cells. In tumor-bearing nude mice model, DHA significantly inhibited the growth of esophageal squamous cancer xenografts, and downregulated the expression of SP1 and hTERT protein, while no side effects were observed from heart, kidney, liver, and lung tissues by HE stain. Conclusion: hTERT plays an oncogenic role in esophageal squamous cancer and might be a therapeutic target of DHA through regulating ROS/SP1 pathway.

Keywords:  dihydroartemisinin; esophageal squamous cancer; reactive oxygen species; specificity protein 1; telomerase reverse transcriptase

DOI:  https://doi.org/10.3389/fphar.2021.769787
Oxid Med Cell Longev. 2021 ;2021 2800706

Broussochalcone A Induces Apoptosis in Human Renal Cancer Cells via ROS Level Elevation and Activation of FOXO3 Signaling Pathway.

Han Ki Lee, Hyo Sun Cha, Myeong Jin Nam, Kyungmoon Park, Yung-Hun Yang, Jongsung Lee, See-Hyoung Park.

Broussochalcone A (BCA) is a chalcone compound extracted from the cortex of Broussonetiapapyrifera (L.) Ventenat that exerts various effects, such as potent antioxidant, antiplatelet, and anticancer effects. However, the effects of BCA against cancers have been seldom studied. This study is aimed at demonstrating the apoptotic mechanisms of BCA in A498 and ACHN cells, which are two types of human renal cancer cell lines. MTT, cell counting, and colony formation assays indicated that BCA treatment inhibited cell viability and cell growth. Further, cell cycle analysis revealed that BCA induced cell cycle arrest at the G2/M phase. Annexin V/PI staining and TUNEL assays were performed to determine the apoptotic effects and DNA fragmentation after treatment with BCA. Based on western blot analysis, BCA induced the upregulation of cleaved PARP, FOXO3, Bax, p21, p27, p53, phosphorylated p53 (ser15, ser20, and ser46), and active forms of caspase-3, caspase-7, and caspase-9 proteins, but downregulated the proforms of the proteins. The expression levels of pAkt, Bcl-2, and Bcl-xL were also found to be downregulated. Western blot analysis of nuclear fractionation results revealed that BCA induced the nuclear translocation of FOXO3, which might be induced by DNA damage owing to the accumulation of reactive oxygen species (ROS). Elevated intracellular ROS levels were also found following BCA treatment. Furthermore, DNA damage was detected after BCA treatment using a comet assay. The purpose of this study was to elucidate the apoptotic effects of BCA against renal cancer A498 and ACHN cells. Collectively, our study findings revealed that the apoptotic effects of BCA against human renal cancer cells occur via the elevation of ROS level and activation of the FOXO3 signaling pathway.

DOI: https://doi.org/10.1155/2021/2800706
Int J Mol Sci. 2021 Oct 29. pii: 11772. [Epub ahead of print]22(21):

Benzyl Isothiocyanate, a Vegetable-Derived Compound, Induces Apoptosis via ROS Accumulation and DNA Damage in Canine Lymphoma and Leukemia Cells.

Marta Henklewska, Aleksandra Pawlak, Rong-Fang Li, Jine Yi, Iwona Zbyryt, Bożena Obmińska-Mrukowicz.

  Treatment of neoplastic diseases in companion animals is one of the most important problems of modern veterinary medicine. Given the growing interest in substances of natural origin as potential anti-cancer drugs, our goal was to examine the effectiveness of benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, against canine lymphoma and leukemia. These are the one of the most common canine cancer types, and chemotherapy is the only treatment option. The study involved established cell lines originating from various hematopoietic malignancies: CLBL-1, GL-1, CLB70 and CNK-89, immortalized noncancerous cell lines: MDCK and NIH-3T3 and canine peripheral blood mononuclear cells (PBMCs). The cytotoxic activity of BITC, apoptosis induction, caspase activity and ROS generation were evaluated by flow cytometry. H2AX phosphorylation was assessed by western blot. The study showed that the compound was especially active against B lymphocyte-derived malignant cells. Their death resulted from caspase-dependent apoptosis. BITC induced ROS accumulation, and glutathione precursor N-acetyl-l-cysteine reversed the effect of the compound, thus proving the role of oxidative stress in BITC activity. In addition, exposure to the compound induced DNA damage in the tested cells. This is the first study that provides information on the activity of BITC in canine hematopoietic malignancies and suggests that the compound may be particularly useful in B-cell neoplasms treatment.

Keywords:  BITC; anti-cancer drugs; cancer treatment; canine cancers; oxidative stress

DOI:  https://doi.org/10.3390/ijms222111772
Front Pharmacol. 2021 ;12 764015

Aberrant ROS Mediate Cell Cycle and Motility in Colorectal Cancer Cells Through an Oncogenic CXCL14 Signaling Pathway.

Jun Zeng, Mei Li, Jun-Yu Xu, Heng Xiao, Xian Yang, Jiao-Xiu Fan, Kang Wu, Shuang Chen.

  Background: Reactive oxygen species (ROS) act as signal mediators to induce tumorigenesis. Objective: This study aims to explore whether chemokine CXCL14 is involved in the proliferation and migration of ROS-induced colorectal cancer (CRC) cells. Methods: The proliferative and migratory capacities of CRC cells treated with or without H2O2 were measured by various methods, including the CKK-8 assay, colony formation assay, flow cytometry, wounding healing assay, and migration assay. Results: The results revealed that H2O2 promoted the proliferation and migration of CRC cells by regulating the cell cycle progression and the epithelial to mesenchymal transition (EMT) process. Furthermore, we noted that the expression level of CXCL14 was elevated in both HCT116 cells and SW620 cells treated with H2O2. An antioxidant N-Acetyl-l-cysteine (NAC) pretreatment could partially suppress the CXCL14 expression in CRC cells treated with H2O2. Next, we constructed CRC cell lines stably expressing CXCL14 (HCT116/CXCL14 and SW620/CXCL14) and CRC cell lines with empty plasmid vectors (HCT116/Control and SW620/Control) separately. We noted that both H2O2 treatment and CXCL14 over-expression could up-regulate the expression levels of cell cycle-related and EMT-related proteins. Moreover, the level of phosphorylated ERK (p-ERK) was markedly higher in HCT116/CXCL14 cells when compared with that in HCT116/Control cells. CXCL14-deficiency significantly inhibited the phosphorylation of ERK compared with control (i.e., scrambled shNCs). H2O2 treatment could partially restore the expression levels of CXCL14 and p-ERK in HCT116/shCXCL14 cells. Conclusion: Our studies thus suggest that aberrant ROS may promote colorectal cancer cell proliferation and migration through an oncogenic CXCL14 signaling pathway.

Keywords:  CXCL14; ROS; cell cycle; colorectal cancer; migration

DOI:  https://doi.org/10.3389/fphar.2021.764015
Nanotechnology. 2021 Nov 08.

DOX-loaded silver nanotriangles and photothermal therapy exert a synergistic antibreast cancer effect via ROS/ERK1/2 signaling pathway.

Fan Li, Huiquan Yang, Yuyu Cao, Dongdong Li, Jing Ma, Peidang Liu.

  The combination of multiple therapies has been proved to be more effective than a single therapy for many cancers. This study aimed to investigate the synergistic antibreast cancer effect of doxorubicin-loaded silver nanotriangles (DOX-AgNTs) combined with near-infrared (NIR) irradiation and explore the underlying mechanism. AgNTs were prepared by a chemical method and DOX was loaded via electrostatic adsorption. Characterization was performed by transmission electron microscopy, ultraviolet-visible spectroscopy and dynamic light scattering. The viability of MDA-MB-231 cells was detected by using MTT assay to evaluate the synergistic anticancer effect of DOX-AgNTs combined with NIR irradiation. The intracellular reactive oxygen species (ROS) level and cell apoptosis were analyzed by ﬂow cytometry. Mitochondrial membrane potential (MMP) was measured with fluorescence microscopy. The mechanism was further investigated with ROS scavenger N-acetylcysteine and specific inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2), C-jun N-terminal kinase and p38 pathways. Characterization results revealed that the prepared AgNTs were mostly triangular and the mean edge length was about 126 nm. The combination of DOX-AgNTs and NIR exhibited a superior synergistic anticancer effect over single DOX-AgNTs or photothermal therapy. N-acetylcysteine and ERK1/2 inhibitor U0126 were found to significantly rescue the decreased cell viability, declined MMP and increased apoptosis induced by the combined treatment. Our results suggested that DOX-AgNTs combined with photothermal therapy performed a synergistic antibreast cancer effect. The synergy might be closely associated with the excessive production of ROS, changed MMP and the activation of ERK1/2 signaling pathway. These findings might provide a new perspective for the development of breast cancer treatments with excellent efficacy.

Keywords:  Doxorubicin; breast cancer; photothermal therapy; silver nanotriangles; synergy

DOI:  https://doi.org/10.1088/1361-6528/ac378c
Protein Pept Lett. 2021 Nov 04.

Oxidative Stress Induced Cell Cycle Arrest: Potential Role of PRX-2 and GSTP-1 as Therapeutic Targets in Hepatocellular Carcinoma.

Abeer Mohsin, Kanwal Haneef, Amber Ilyas, Shamshad Zarina, Zehra Hashim.

  BACKGROUND: The increasing incidence and mortality rate of HCC is a major concern, especially for developing countries of the world. Hence, extensive research is being carried out in order to explore new approaches for developing successful therapeutic strategies for HCC. The controversial role of oxidative stress in the prognosis and treatment of various diseases such as cancer has become the area of great interest and intrigue for many scientists throughout the world.OBJECTIVE: We aim to investigate the role of induced oxidative stress on the suppression of HCC Huh-7 cancerous cells as therapeutic approach.
METHODS: Induction of oxidative stress via H2O2 treatment produced cell cytotoxicity in a dose dependent manner and also led to the over expression of GSTP-1 and PRX-2. The expression of GSTP-1 and PRX-2 was compared in HCC Huh-7 treated, untreated cells and normal hepatocytes using immunocytochemistry. Furthermore, the effects of oxidative stress on cell cycle arrest were also studied through flow cytometry.
RESULTS: Our study demonstrated the inhibition of cancer cell proliferation as a result of H2O2 induction by arresting the cell cycle at G2 phase.
CONCLUSION: The induction of oxidative stress could be a potential therapeutic approach for treating HCC in the future. GSTP-1 and PRX-2 can serve as substantial therapeutic targets for the treatment of HCC.

Keywords:  Cell Cycle; H2O2; Hepatocellular carcinoma; cancer therapy; glutathione S-transferase; oxidative stress; peroxiredoxin-2; reactive oxygen species

DOI:  https://doi.org/10.2174/0929866528666211105105953
Eur J Cell Biol. 2021 Nov 03. pii: S0171-9335(21)00032-7. [Epub ahead of print]100(7-8): 151181

ROS-Nrf2 pathway mediates the development of TGF-β1-induced epithelial-mesenchymal transition through the activation of Notch signaling.

Kai Yazaki, Yosuke Matsuno, Kazufumi Yoshida, Mingma Sherpa, Masayuki Nakajima, Masashi Matsuyama, Takumi Kiwamoto, Yuko Morishima, Yukio Ishii, Nobuyuki Hizawa.

  Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells transform to acquire mesenchymal phenotypes. Accumulating evidence indicate the involvement of EMT in the progression of malignant diseases. Notch signaling mediates TGF-β1-induced EMT through direct transcriptional activation of Snai1. The molecular mechanism how TGF-β1 activates Notch signaling, however, remains unknown. In this study, we show a pivotal role for reactive oxygen species (ROS)-Nrf2 pathway in TGF-β1-induced Notch signaling activation and EMT development. TGF-β1 induces Nrf2 activation through ROS production. Inhibiting Nrf2 activation either by reducing ROS levels by N-acetylcysteine or by knocking down of Nrf2 by small interfering RNA attenuated both Notch signaling activation and EMT development. TGF-β1 induced the transcription of Notch4 via Nrf2-dependent promoter activation. In conclusion, our study indicates the ROS-Nrf2 pathway mediates the development of TGF-β1-induced EMT through the activation of Notch signaling.

Keywords:  A549; EMT; Notch signaling; Nrf2; ROS; TGF-β1

DOI:  https://doi.org/10.1016/j.ejcb.2021.151181
Biomark Res. 2021 Nov 06. 9(1): 82

The role of ferroptosis in lung cancer.

Sikai Wu, Chengchu Zhu, Daolin Tang, Q Ping Dou, Jianfei Shen, Xin Chen.

  Lung cancer is one of the most common cancers in the world. Although medical treatment has made impressive progress in recent years, it is still one of the leading causes of cancer-related deaths in men and women. Ferroptosis is a type of non-apoptotic cell death modality, usually characterized by iron-dependent lipid peroxidation, rather than caspase-induced protein cleavage. Excessive or lack of ferroptosis is associated with a variety of diseases, including cancer and ischaemia-reperfusion injury. Recent preclinical evidence suggests that targeting ferroptotic pathway is a potential strategy for the treatment of lung cancer. In this review, we summarize the core mechanism and regulatory network of ferroptosis in lung cancer cells, and highlight ferroptosis induction-related tumor therapies. The reviewed information may provide new insights for targeted lung cancer therapy.

Keywords:  Ferroptosis; Lipid peroxidation; Lung cancer; ROS; iron

DOI:  https://doi.org/10.1186/s40364-021-00338-0
Int J Mol Sci. 2021 Oct 29. pii: 11760. [Epub ahead of print]22(21):

15d-PGJ2 Promotes ROS-Dependent Activation of MAPK-Induced Early Apoptosis in Osteosarcoma Cell In Vitro and in an Ex Ovo CAM Assay.

Mateja Mikulčić, Nassim Ghaffari Tabrizi-Wizsy, Eva M Bernhart, Martin Asslaber, Christopher Trummer, Werner Windischhofer, Wolfgang Sattler, Ernst Malle, Andelko Hrzenjak.

  Osteosarcoma (OS) is the most common type of bone tumor, and has limited therapy options. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has striking anti-tumor effects in various tumors. Here, we investigated molecular mechanisms that mediate anti-tumor effects of 15d-PGJ2 in different OS cell lines. Human U2-OS and Saos-2 cells were treated with 15d-PGJ2 and cell survival was measured by MTT assay. Cell proliferation and motility were investigated by scratch assay, the tumorigenic capacity by colony forming assay. Intracellular ROS was estimated by H2DCFDA. Activation of MAPKs and cytoprotective proteins was detected by immunoblotting. Apoptosis was detected by immunoblotting and Annexin V/PI staining. The ex ovo CAM model was used to study growth capability of grafted 15d-PGJ2-treated OS cells, followed by immunohistochemistry with hematoxylin/eosin and Ki-67. 15d-PGJ2 substantially decreased cell viability, colony formation and wound closure capability of OS cells. Non-malignant human osteoblast was less affected by 15d-PGJ2. 15d-PGJ2 induced rapid intracellular ROS production and time-dependent activation of MAPKs (pERK1/2, pJNK and pp38). Tempol efficiently inhibited 15d-PGJ2-induced ERK1/2 activation, while N-acetylcystein and pyrrolidine dithiocarbamate were less effective. Early but weak activation of cytoprotective proteins was overrun by induction of apoptosis. A structural analogue, 9,10-dihydro-15d-PGJ2, did not show toxic effects in OS cells. In the CAM model, we grafted OS tumors with U2-OS, Saos-2 and MG-63 cells. 15d-PGJ2 treatment resulted in significant growth inhibition, diminished tumor tissue density, and reduced tumor cell proliferation for all cell lines. Our in vitro and CAM data suggest 15d-PGJ2 as a promising natural compound to interfere with OS tumor growth.

Keywords:  15d-PGJ2; CAM assay; apoptosis; osteosarcoma; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms222111760
Chemistry. 2021 Nov 10.

Highly Efficient Ir(III)-coumarin Photo-redox Catalyst for Synergetic Multi-mode Cancer Photo-therapy.

Huaiyi Huang, Zhongxian Fan, Jiaen Xie, Tumpa Sadhukhan, Chao Liang, Can Huang, Wenqing Li, Tingxuan Li, Pingyu Zhang, Samya Banerjee, Krishnan Raghavachari.

  Novel Ir(III) photo-redox catalysts [Ir(C^N) 2 (N^N^N)] + ( Ir1-4 ) employing bidentate terpyridine-based ligands were synthesized and evaluated for photo-catalytic cancer therapy. The coumarin functionalized photo-catalysts ( Ir1 - Ir3 ) showed excellent photo-stability with strong visible light absorption between 400-550 nm. Upon light irradiation (465 and 525 nm), Ir1 - Ir3 synergistically generated singlet oxygen and induced rapidly photo-catalytic oxidation of cellular coenzymes NAD(P)H. Ir1 - Ir3 showed time-dependent cellular uptake with excellent intracellular retention efficiency. Upon green light irradiation (525 nm), Ir2 provided a much higher photo-index (PI = 793) than the clinically used photosensitizer, 5-aminolevulinicacid (5-ALA, PI > 30) against HeLa cancer cells. The observed necro-apoptotic anticancer activity of Ir2 was due to the photo-triggered intracellular redox imbalance (by NAD(P)H oxidation and ROS generation) and change in the mitochondrial membrane potential. Remarkably, Ir2 showed in-vivo photo-induced catalytic anticancer activity in mouse models.

Keywords:  Iridium complex * anticancer * photo catalysis * photodynamic therapy * NADH

DOI:  https://doi.org/10.1002/chem.202103346
Metab Brain Dis. 2021 Nov 08.

Selective in vitro anticancer effect of blueberry extract (Vaccinium virgatum) against C6 rat glioma: exploring their redox status.

Larissa Menezes da Silveira, Nathalia Stark Pedra, Natália Pontes Bona, Luiza Spohr, Francieli da Silva Dos Santos, Juliane Torchelsen Saraiva, Fernando Lopez Alvez, Bernardo de Moraes Meine, Roselia Maria Spanevello, Francieli Moro Stefanello, Mayara Sandrielly Pereira Soares.

  The aim of this study was to investigate the anticancer potential of blueberry extract (Vaccinium virgatum) against a C6 rat glioma lineage. Cultures of the C6 cells were exposed to blueberry extract at concentrations of 50 to 600 µg/mL for 12, 24, 48, or 72 h and then evaluated for cell viability, proliferation, migration, colony formation and oxidative stress. We also evaluated the effects of blueberry extract on primary rat cortical astrocytes. Our results show that treatment with blueberry extract did not alter the viability or proliferation of normal primary astrocytes but it did significantly reduce the viability in 21.54 % after 48 h and proliferation in 8.59 % after 24 h of C6 cells at 200 µg/mL. We also observed a reduction in the size of the colonies of 29.99 % at 100 µg/mL when compared to the control cells and cell migration was also reduced at 50 µg/mL. After 72 h, there was a reduction in the reactive oxygen species levels ranging from 46.26 to 34.73 %, in addition to a 380.2 % increase in total thiol content. Superoxide dismutase, catalase, and glutathione S-transferase activities were also enhanced when compared to the control. Taken together this data suggests that blueberry extract exerts some selective anticancer activity in C6 glioma cells.

Keywords:  Antioxidants; Cancer; Glioblastoma; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-021-00867-5