bims-rehoca 2021-10-31 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–10–31
27 papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex.
Tumor Microenvironment-activated Reactive Oxygen Species Amplifier for Enzymatic Cascade Cancer Starvation/Chemodynamic /Immunotherapy.
Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells.
Riluzole: A neuroprotective drug with potential as a novel anti‑cancer agent (Review).
A Novel Fluorescent Dye Invades Mitochondria to Selectively Kill Cancer Stem Cells via Increased ROS Production.
High Concentration of Iopromide Induces Apoptosis and Autophagy in Human Embryonic Kidney Cells via Activating a ROS-dependent Cellular Stress Pathway.
18β-Glycyrrhetinic Acid Has Anti-Cancer Effects via Inducing Apoptosis and G2/M Cell Cycle Arrest, and Inhibiting Migration of A549 Lung Cancer Cells.
TEOA Promotes Autophagic Cell Death via ROS-Mediated Inhibition of mTOR/p70S6k Signaling Pathway in Pancreatic Cancer Cells.
NICOTINAMIDE EXERTS A PROTECTIVE EFFECT FROM UV-INDUCED STRESS DAMAGES ON HUMAN PRIMARY KERATINOCYTES FROM CANCERIZATION FIELD.
Chronic cadmium exposure induces epithelial mesenchymal transition in prostate cancer cells through a TGF-β-independent, endoplasmic reticulum stress induced pathway.
A novel biphenyl diester derivative, AB38b, inhibits glioblastoma cell growth via the ROS-AKT/mTOR pathway.
Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress.
An ROS-activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy.
Effects of troponoids on mitochondrial function and cytotoxicity.
Hafnium Oxide-Based Nanoplatform for Combined Chemoradiotherapy.
Near-infrared light-triggered synergistic antitumor therapy based on hollow ZIF-67-derived Co3S4-indocyanine green nanocomplex as a superior reactive oxygen species generator.
Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.
Mitophagy Induction by ROS-PINK1 Signaling Protects Head and Neck Cancer From Radiotherapy.
YBX1 knockdown induces renal cell carcinoma cell apoptosis via Kindlin-2.
Docosahexaenoic Acid Inhibits Cytokine Expression by Reducing Reactive Oxygen Species in Pancreatic Stellate Cells.
A Novel Ferroptosis-Related 4-Gene Prognostic Signature for Cholangiocarcinoma and Photodynamic Therapy.
Understanding of catalytic ROS generation from defect-rich graphene quantum-dots for therapeutic effects in tumor microenvironment.
Lung tumor growth promotion by tobacco-specific nitrosamines involves the β2-adrenergic receptors-dependent stimulation of mitochondrial REDOX signaling.
Serum Reactive Oxygen Species Modulator 1 as a Novel Predictive Biomarker for Resected Lung Adenocarcinoma: A Retrospective Pilot Study.
Nuclear factor erythroid 2-related factor 2 in human papillomavirus-related cancers.
An antiinflammatory Fe3O4-porphyrin nanohybrid capable of apoptosis through upregulation of p21 kinase inhibitor having immunoprotective properties under anti-cancer PDT conditions.
THAP9-AS1 Promotes Tumorigenesis and Reduces ROS Generation through the JAK2/STAT3 Signaling Pathway by Increasing SOCS3 Promoter Methylation in Osteosarcoma.

Mol Med Rep. 2021 Dec;pii: 873. [Epub ahead of print]24(6):

Ginsenoside Rh2 stimulates the production of mitochondrial reactive oxygen species and induces apoptosis of cervical cancer cells by inhibiting mitochondrial electron transfer chain complex.

Ying Liu, Shiting Yu, Xin Xing, Juhui Qiao, Yiqiu Yin, Jiawen Wang, Meichen Liu, Wei Zhang.

  Ginsenoside Rh2 (G‑Rh2) is a monomeric compound that extracted from ginseng and possesses anti‑cancer activities both in vitro and in vivo. Previously, we reported that G‑Rh2 induces apoptosis in HeLa cervical cancer cells and that the process was related to reactive oxygen species (ROS) accumulation and mitochondrial dysfunction. However, the upstream mechanisms of G‑Rh2, along with its cellular targets, remain to be elucidated. In the present study, the Cell Counting Kit‑8 assay, flow cytometry and Hoechst staining revealed that G‑Rh2 significantly inhibited cell viability and induced apoptosis of cervical cancer cells. However, G‑Rh2 was demonstrated to be non‑toxic to End1/e6e7 cells. JC‑1, rhodamine 123 staining, oxidative phosphorylation and glycolysis capacity assays demonstrated that G‑Rh2 exposure caused an immediate decrease in mitochondrial transmembrane potential due to its inhibition of mitochondrial oxidative phosphorylation, as well as glycolysis, both of which reduced cellular ATP production. Western blotting and electron transport chain (ETC) activity assays revealed that G‑Rh2 significantly inhibited the activity of ETC complexes I, III and V. Overexpression of ETC complex III partially significantly restored mitochondrial ROS and inhibited the apoptosis of cervical cancer cells induced by G‑Rh2. The predicted results of binding energy in molecular docking, confirmed that G‑Rh2 was highly likely to induce mitochondrial ROS production and promote cell apoptosis by targeting the ETC complex, especially for ETC complex III. Taken together, the present results revealed the potential anti‑cervical cancer activity of G‑Rh2 and provide direct evidence for the contribution of impaired ETC complex activity to cervical cancer cell death.

Keywords:  ginsenoside Rh2; mitochondria; mitochondrial electron transfer chain complexes; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.3892/mmr.2021.12513
Adv Mater. 2021 Oct 26. e2106010

Tumor Microenvironment-activated Reactive Oxygen Species Amplifier for Enzymatic Cascade Cancer Starvation/Chemodynamic /Immunotherapy.

Man Wang, Mengyu Chang, Chunxia Li, Qing Chen, Zhiyao Hou, Bengang Xing, Jun Lin.

  At present, some progresses have been made in the field of cancer theranostics based on nanocatalysts (NCs), but achieving the precisive theranostics in response to specific tumor microenvironment (TME) remains a major challenge. Herein, we engineered a TME responsive upconversion nanoparticles (UCNPs)-based smart UCNPs@Cu-Cys-GOx (UCCG) nanosystem, which combines natural enzymes and nanozymes so as to in situ amplify reactive oxygen species (ROS) generation for cancer starvation/chemodynamic/immunotherapy. One of the biggest merits of this material is that it can preserve inert (off) in normal tissues, and only in TME can it be specifically activated (on) through a series of enzymatic cascade to boost ROS production via a strategy of open source (H2 O2 self-supplying ability) and reduce expenditure (GSH consuming ability). More importantly, the enhanced oxidative stress by UCCG NCs reverses the immunosuppressive TME, and facilitates antitumor immune responses. Meanwhile, the starvation/chemodynamic synergistic therapy triggered by UCCG combined with PD-L1 antibody effectively inhibited the growth of primary tumors and cancer metastasis. In addition, the UCNPs in UCCG presented upconversion luminescence enhancement, which can be exploited to visualize the reinforced ROS generation in real time. Collectively, this work provided an original method for the devisal and exploitation of UCNPs based catalytic immunotherapy. This article is protected by copyright. All rights reserved.

Keywords:  ROS amplifier; enzymatic cascade reaction; immune system activation; synergistic therapy; upconversion luminescence

DOI:  https://doi.org/10.1002/adma.202106010
Oxid Med Cell Longev. 2021 ;2021 1783485

Bavachin Induces Ferroptosis through the STAT3/P53/SLC7A11 Axis in Osteosarcoma Cells.

Yi Luo, Xu Gao, Luetao Zou, Miao Lei, Junming Feng, Zhenming Hu.

Ferroptosis is a new form of regulated cell death, which is mediated by intracellular iron. Although it is reported that bavachin has antitumour effects on several tumour cells and prompts the reactive oxygen species (ROS) generation, it is unclear whether ferroptosis can be induced by bavachin in osteosarcoma (OS) cells. In this study, we found that bavachin inhibits the viability of MG63 and HOS OS cell lines along with an increase in the ferrous iron level, ROS accumulation, malondialdehyde overexpression, and glutathione depletion. Moreover, iron chelators (deferoxamine), antioxidants (Vit E), and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) reverse bavachin-induced cell death. Bavachin also altered the mitochondrial morphology of OS cells, leading to smaller mitochondria, higher density of the mitochondrial membrane, and reduced mitochondrial cristae. Further investigation showed that bavachin upregulated the expression of transferrin receptor, divalent metal transporter-1, and P53, along with downregulating the expression of ferritin light chain, ferritin heavy chain, p-STAT3 (705), SLC7A11, and glutathione peroxidase-4 in OS cells. More importantly, STAT3 overexpression, SLC7A11 overexpression, and pretreatment with pifithrin-α (P53 inhibitor) rescued OS cell ferroptosis induced by bavachin. The results show that bavachin induces ferroptosis via the STAT3/P53/SLC7A11 axis in OS cells.

DOI: https://doi.org/10.1155/2021/1783485
Int J Oncol. 2021 Nov;pii: 95. [Epub ahead of print]59(5):

Riluzole: A neuroprotective drug with potential as a novel anti‑cancer agent (Review).

Angelina Blyufer, Sonam Lhamo, Cassey Tam, Iffat Tariq, Thongthai Thavornwatanayong, Shahana S Mahajan.

  Riluzole, a glutamate release inhibitor, has been in use for the treatment of amyotrophic lateral sclerosis for over two decades since its approval by the Food and Drug Administration. Recently, riluzole has been evaluated in cancer cells and indicated to block cell proliferation and/or induce cell death. Riluzole has been proven effective as an anti‑neoplastic drug in cancers of various tissue origins, including the skin, breast, pancreas, colon, liver, bone, brain, lung and nasopharynx. While cancer cells expressing glutamate receptors frequently respond to riluzole treatment, numerous types of cancer cell lacking glutamate receptors unexpectedly responded to riluzole treatment as well. Riluzole was demonstrated to interfere with glutamate secretion, growth signaling pathways, Ca2+ homeostasis, glutathione synthesis, reactive oxygen species generation and integrity of DNA, as well as autophagic and apoptotic pathways. Of note, riluzole is highly effective in inducing cell death in cisplatin‑resistant lung cancer cells. Furthermore, riluzole pretreatment sensitizes glioma and melanoma to radiation therapy. In addition, in triple‑negative breast cancer, colorectal cancer, melanoma and glioblastoma, riluzole has synergistic effects in combination with select drugs. In an effort to highlight the therapeutic potential of riluzole, the current study reviewed the effect and outcome of riluzole treatment on numerous cancer types investigated thus far. The mechanism of action and the various molecular pathways affected by riluzole are discussed.

Keywords:  DNA damage; apoptosis; cell cycle arrest; combination therapy; glutamate secretion and signaling; reactive oxygen species; riluzole

DOI:  https://doi.org/10.3892/ijo.2021.5275
Bioinorg Chem Appl. 2021 ;2021 4763944

A Novel Fluorescent Dye Invades Mitochondria to Selectively Kill Cancer Stem Cells via Increased ROS Production.

Bei-Bei Zhang, Jun-Gang Liu, Xian-Yu Bai, Yuan-Jiao Huang, Ning Xu, Tao Ren.

Development of multiple agents has a significant impact on the cancer diagnosis and therapy. Several fluorescent dyes including near-infrared (NIR) fluorescent agents have been already well studied in the field of photodynamic therapy (PDT). In the present study, we reported a novel fluorescent dye could obviously inhibit cancer cell proliferation with slight toxic effects on the biological organism. Furthermore, it displayed selective staining on cancer cells, particularly on cancer stem cells (CSCs), rather than normal cells. Mechanically, this dye preferred to invading mitochondria of cancer cells and inducing overwhelming reactive oxygen species (ROS) production. The in vivo experiments further demonstrated that this dye could image cancer cells and even CSCs in a short-time intratumor injection manner using a zebrafish model and subsequently inhibit cancer cell proliferation after a relatively long-time drug exposure. Taken together, the future development of this agent will promise to make an essential contribution to the cancer diagnosis and therapeutics.

DOI: https://doi.org/10.1155/2021/4763944
In Vivo. 2021 Nov-Dec;35(6):35(6): 3221-3232

High Concentration of Iopromide Induces Apoptosis and Autophagy in Human Embryonic Kidney Cells via Activating a ROS-dependent Cellular Stress Pathway.

Yuh-Feng Tsai, Jai-Sing Yang, Fuu-Jen Tsai, Yih-Dih Cheng, Yu-Jen Chiu, Shih-Chang Tsai.

   BACKGROUND/AIM: The use of iodinated contrast media may impair renal function. However, no report has addressed the nephrotoxicity of high doses of iodinated contrast media in normal kidney cells and its associated molecular mechanisms.
MATERIALS AND METHODS: Cell proliferation was assessed using the MTT assay. Cell death was evaluated through examining the morphological changes and TUNEL assay. Autophagy was detected through acridine orange staining and lysotracker staining. Reactive oxygen species production and AKT kinase activity were examined.
RESULTS: Iopromide induced cell death and triggered apoptosis and autophagy in HEK 293 cells. Cell viability was significantly restored in the presence of a pan-caspase inhibitor or a ROS scavenger, N-acetyl-L-cysteine. AKT kinase activity was found to be reduced in iopromide-treated HEK 293 cells.
CONCLUSION: High concentrations of iopromide induce cell damage, apoptosis, and autophagy through down-regulating AKT and ROS-activated cellular stress pathways in HEK 293 cells.

Keywords:  Iopromide; apoptosis; autophagy; human embryonic kidney 293 cells; reactive oxygen species

DOI:  https://doi.org/10.21873/invivo.12617
Onco Targets Ther. 2021 ;14 5131-5144

18β-Glycyrrhetinic Acid Has Anti-Cancer Effects via Inducing Apoptosis and G2/M Cell Cycle Arrest, and Inhibiting Migration of A549 Lung Cancer Cells.

Ying-Hua Luo, Cheng Wang, Wan-Ting Xu, Yu Zhang, Tong Zhang, Hui Xue, Yan-Nan Li, Zhong-Ren Fu, Ying Wang, Cheng-Hao Jin.

   Background: 18β-glycyrrhetinic acid (18β-Gly), which is extracted from licorice root, has various pharmacological properties; however, its anti-cancer effects on lung cancer cells have not been fully established.
Purpose: In this study, we investigated the underlying molecular mechanisms of 18β-Gly.
Results: Our results showed that 18β-Gly had significant cytotoxic effects and no apparent side effects. 18β-Gly induced mitochondria-dependent apoptosis of A549 lung cancer cells. In addition, after treatment with 18β-Gly, intracellular reactive oxygen species (ROS) levels were significantly increased, and G2/M cell cycle arrest and inhibition of cell migration were induced via the mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa (NF-κB) signaling pathways. After pretreatment with the ROS scavenger N-acetyl-L-cysteine or MAPK inhibitors, the expression levels of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase, inhibitor of nuclear factor kappa B, cleaved caspase-3 (cle-cas-3), cleaved poly (ADP ribose) polymerase (cle-PARP), p-p53, p27, p21, and E-cadherin were decreased; and levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, NF-κB, Bcl-2, cyclin B1, cyclase-dependent kinase 1/2 (CDK1/2), N-cadherin, vimentin, and snail homolog 1 (SNAI 1) were increased. In addition, the percentage of cells in the G2/M phase was decreased, and inhibition of migration was reduced.
Conclusion: In summary, 18β-Gly induced apoptosis and G2/M cell cycle arrest and inhibited migration via the ROS/MAPK/STAT3/NF-κB signaling pathways in A549 lung cancer cells. Therefore, 18β-Gly is a novel promising candidate for the treatment of lung cancer.

Keywords:  18β-glycyrrhetinic acid; ROS; apoptosis; cell cycle arrest; cell migration; lung cancer

DOI:  https://doi.org/10.2147/OTT.S322852
Front Cell Dev Biol. 2021 ;9 734818

TEOA Promotes Autophagic Cell Death via ROS-Mediated Inhibition of mTOR/p70S6k Signaling Pathway in Pancreatic Cancer Cells.

Chen Yang, Yanchun Li, Wanye Hu, Xu Wang, Jiayu Hu, Chen Yuan, Chaoting Zhou, Hairui Wang, Jing Du, Ying Wang, Xiangmin Tong.

  Pancreatic cancer is a common malignant tumor with high mortality, and novel therapeutic options have focused on ameliorating its poor prognosis. TEOA, a traditional Chinese herbal medicine, exhibits anti-inflammatory and anti-cancer activities. Our recent study has shown that TEOA inhibits proliferation and induces DNA damage in diffuse large B-cell lymphoma cells by activating the ROS-mediated p38 MAPK pathway. However, its effects on pancreatic cancer cells remain unknown. In the present study, we evaluated the effects of TEOA on the proliferation, migration of pancreatic cancer cells and explored the possible underlying mechanism of action. We found that TEOA significantly inhibited the proliferation and migration of pancreatic cancer cells in a time- and dose-dependent manner. Mechanistically, TEOA significantly induced mitochondrial dysfunction in PANC1 and SW1990 cells, as evidenced by the collapse of the mitochondrial membrane potential, exhausted ATP level, and excessive accumulation of intracellular ROS. Notably, our further experiments showed that TEOA induced autophagic cell death in pancreatic ductal adenocarcinoma cells by inactivating the ROS-dependent mTOR/p70S6k signaling pathway. More importantly, both pharmacological or genetic blocking of the autophagic flux signal could partly restore the cytotoxicity of TEOA, whereas activation of autophagy by rapamycin or EBSS induced starvation facilitated the cytotoxicity of TEOA. Concomitantly, N-acetylcysteine, a ROS scavenger, abolished the inhibition of the mTOR signaling pathway, thus preventing autophagy and restoring cell viability. Taken together, our results reveal that TEOA can lead to ROS-dependent autophagic cell death of pancreatic cancer cells by inducing mitochondrial dysfunction, which might be a promising therapeutic agent for pancreatic cancer.

Keywords:  ROS; TEOA; autophagy; mTOR; mitochondria injury; pancreatic cancer cells

DOI:  https://doi.org/10.3389/fcell.2021.734818
J Invest Dermatol. 2021 Oct 22. pii: S0022-202X(21)02385-X. [Epub ahead of print]

NICOTINAMIDE EXERTS A PROTECTIVE EFFECT FROM UV-INDUCED STRESS DAMAGES ON HUMAN PRIMARY KERATINOCYTES FROM CANCERIZATION FIELD.

Lara Camillo, Laura C Gironi, Elisa Zavattaro, Elia Esposto, Paola Savoia.

  Ultraviolet B (UVB) radiation directly damages DNA, increases reactive oxygen species (ROS) and nitric oxide (NO) release, and promotes inflammation leading to genomic instability and cell death. Nicotinamide (NAM) is the precursor of NAD, essential for cell energy production and DNA damage repair. NAM protects HaCat cells from UV-induced impairment; however, little is known about its effects on human primary keratinocytes (HPKs) and those isolated from field cancerization (FC-HPKs). We examined the role of NAM against UV-induced oxidative stress damages in FC-HPKs, isolated from precancerous lesions and skin cancers, and in normal epidermal keratinocytes (NHEK). Cells were treated for 18, 24, and 48 hours with NAM (5, 25, and 50 μM) before UVB irradiation. FC-HPK showed 4-fold higher basal ROS levels, comparing with NHEK; NAM downregulated ROS production only in irradiated FC-HPK, that showed a greater sensibility to UV rays. UV exposure increased OGG1, iNOS and IL-1β expression, an effect counteracted by NAM pre-treatment. Intracellular NO production and DNA damages were inhibited by NAM exposure before irradiation. Collectively, our findings indicate that pre-treatment with 25 μM NAM 24h before UVB irradiation effectively prevents oxidative stress formation, DNA damages, and inflammation in both NHEKs and FC-HPKs.

Keywords:  Nicotinamide; Non-Melanoma Skin Cancers; cancerization field; human primary keratinocytes; oxidative stress; photoprotection; reactive oxygen species (ROS); ultraviolet damage

DOI:  https://doi.org/10.1016/j.jid.2021.10.012
Toxicol Lett. 2021 Oct 20. pii: S0378-4274(21)00860-2. [Epub ahead of print]

Chronic cadmium exposure induces epithelial mesenchymal transition in prostate cancer cells through a TGF-β-independent, endoplasmic reticulum stress induced pathway.

Weirong Hu, Mizhen Xia, Cheng Zhang, Bingdong Song, Zhengmei Xia, Chunyu Guo, Yingying Cui, Weiying Jiang, Shicheng Zhang, Dexiang Xu, Jun Fang.

  In this study, we aimed to elucidate the role of chronic cadmium (Cd) exposure in epithelial-mesenchymal transition (EMT) and thus malignant phenotypic changes of prostate cancer cells. Prostate cancer cells (PC-3 and DU145) were exposed to a non-toxic level (0.5 or 2 μM) of Cd for up to 3 months, which resulted in significantly promoted migration and invasion of the cells. These phenotypic changes were considered to be the consequence of enhanced EMT as evidenced by diminished expression of E-cadherin and increased vimentin expression. Regarding the mechanisms of Cd-induced EMT, we found Smad3 was activated but without upregulation of TGF-β. Alternatively, we found endoplasmic reticulum (ER) stress of prostate cancer cells was significantly evoked, which was parallel with the increased reactive oxygen species (ROS). Removal of ROS by N-acetylcysteine significantly reduced ER stress in prostate cancer cells, followed by the decrease of Smad3 phosphorylation and expression of nuclear Snail, resulting in the inhibition of EMT and malignant phenotypic changes of prostate cancer cells. These findings indicated a new TGF-β independent, ROS-mediated ER stress/Smad signaling pathway in chronic Cd exposure-induced EMT of prostate cancer cells, which could be a novel mechanism involved in cadmium-mediated cancer cells malignant transformation. Accordingly, ROS-induced ERs may become a novel preventive and therapeutic target for cancer.

Keywords:  TGF-β-independent/Smad3 pathway; cadmium; endoplasmic reticulum stress; epithelial-mesenchymal transition; reactive oxygen species

DOI:  https://doi.org/10.1016/j.toxlet.2021.10.007
Biochem Pharmacol. 2021 Oct 20. pii: S0006-2952(21)00411-1. [Epub ahead of print] 114795

A novel biphenyl diester derivative, AB38b, inhibits glioblastoma cell growth via the ROS-AKT/mTOR pathway.

Qingming Meng, Junbo Zhou, Fangting You, Yue Wu, Liquan Yang, Yan Wang, Xu Zhang, Shangfeng Gao, Rutong Yu, Xiaoxing Yin.

  AB38b is a novel biphenyl diester derivative synthesized in our laboratory, and it has been shown to improve the pathology of nephropathy and encephalopathy in diabetic mice. Glioblastoma (GBM) is the most lethal brain tumor, without effective drugs to date. The present study aims at investigating the role of AB38b in GBM growth and revealing the underlying molecular mechanisms. We found that AB38b administration showed a dose- and time-dependent inhibition on cell proliferation in multiple immortalized and primary GBM cell lines, but it had no significant effects on human astrocyte cell line. More importantly, AB38b blocked cell cycle progression, induced early apoptosis, decreased the activity of AKT/mTOR pathway, and increased the generation of reactive oxygen species (ROS) in GBM cells. Interestingly, antioxidant treatments could reverse the AB38b-mediated abovementioned effects; overexpression of constitutively active AKT could partially rescue the suppressive effects of Ab38b on GBM cell proliferation. In addition, AB38b administration inhibited the tumor growth, decreased the activity of AKT/mTOR pathway, and prolonged the survival time in GBM animal models, without any adverse influences on the important organs. These findings suggest that AB38b exerts anti-glioma activity via elevating the ROS generation followed by inhibiting the activity of AKT/mTOR pathway.

Keywords:  AB38b; AKT/mTOR pathway; Apoptosis; G2/M phase; Glioblastoma; Oxidative stress

DOI:  https://doi.org/10.1016/j.bcp.2021.114795
Am J Physiol Cell Physiol. 2021 Oct 27.

Chemotherapy agents reduce protein synthesis and ribosomal capacity in myotubes independent of oxidative stress.

Bin Guo, Devasier Bennet, Daniel J Belcher, Hyo-Gun Kim, Gustavo A Nader.

  Chemotherapeutic agents (CAs) are first-line antineoplastic treatments in a wide variety of cancers. These agents can induce oxidative stress and promote muscle loss. CAs trigger local and systemic oxidative stress by increasing mitochondrial reactive oxygen species (ROS) and thereby stimulate protein breakdown. However, whether CAs can directly impact muscle protein synthesis independent of ROS production is currently unknown. To address this problem, first, we identified the mechanism by which oxidative stress impairs myotube protein synthesis. Transient elevations in ROS production resulted in protein synthesis deficits, reduced ribosomal (r)RNA levels and increased rRNA oxidation. We then investigated the effects of CAs on protein synthesis in the absence of detectable elevations in ROS levels (sub-ROS). Paclitaxel (PTX), Doxorubicin (DXR) and Marizomib (Mzb) diminished protein synthesis and ribosomal capacity, and also impaired transcription of the rRNA genes (rDNA). These results indicate that while oxidative stress disrupted protein synthesis by compromising ribosome quantity and quality, CAs at sub-ROS doses also impaired protein synthesis and ribosomal capacity by reducing rDNA transcription. Therefore, CAs can negatively modulate myotube protein synthesis in a ROS-independent manner by altering the capacity for protein synthesis.

Keywords:  chemotherapy; muscle atrophy; oxidative stress; protein synthesis; ribosomal RNA

DOI:  https://doi.org/10.1152/ajpcell.00116.2021
Adv Healthc Mater. 2021 Oct 28. e2101702

An ROS-activatable Nanoassembly Remodulates Tumor Cell Metabolism for Enhanced Ferroptosis Therapy.

Yuchen Zhang, Liqi Li, Yanan Li, Yang Fei, Chencheng Xue, Xuemei Yao, Youbo Zhao, Xuan Wang, Menghuan Li, Zhong Luo.

  Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide-scavenging mechanisms and the reliance on acidic pH. Herein, we have developed a nanointegrated strategy based on clinically-safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy. We first conjugated ferrocene on PEGylated polyamidoamine dendrimers via ROS-cleavable thioketal linkage, which would further self-assemble with the glutathione (GSH)-depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4-inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4-PAMAM-PEG-TK-Fc@DEM). The nanoassemblies could be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterwards DEM could directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)-mediated antioxidant defense while siMCT4 could block the MCT4-mediated efflux of lactic acid and acidify the intracellular milieu, both of which could improve the ferrocene-catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4-PAMAM-PEG-TK-Fc@DEM nanoplatform demonstrated high ferroptosis-based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability. This article is protected by copyright. All rights reserved.

Keywords:  Ferroptosis sensitization; ROS-activatable nanoassembly; drug delivery; metabolic regulation

DOI:  https://doi.org/10.1002/adhm.202101702
Antimicrob Agents Chemother. 2021 Oct 25. AAC0161721

Effects of troponoids on mitochondrial function and cytotoxicity.

Daniel P Bradley, Austin T O'Dea, Molly E Woodson, Qilan Li, Nathan L Ponzar, Alaina Knier, Bruce L Rogers, Ryan P Murelli, John E Tavis.

The α-hydroxytropolones (αHT) are troponoid inhibitors of hepatitis B virus (HBV) replication that can target the HBV ribonuclease H (RNase H) with sub-micromolar efficacies. αHTs and related troponoids (tropones and tropolones) can be cytotoxic in cell lines as measured by MTS assays that assesses mitochondrial function. Earlier studies suggest that tropolones induce cytotoxicity through inhibition of mitochondrial respiration. Therefore, we screened 35 diverse troponoids for effects on mitochondrial function, mitochondrial:nuclear genome ratio, cytotoxicity, and reactive oxygen species (ROS) production. Troponoids as a class did not inhibit respiration or glycolysis, although the α-ketotropolone subclass did interfere with these processes. The troponoids had no impact on the mitochondrial DNA to nuclear DNA ratio after three days of compound exposure. Patterns of troponoid-induced cytotoxicity among three hepatic cell lines were similar for all compounds, but three potent HBV RNase H inhibitors were not cytotoxic in primary human hepatocytes. Tropolones and αHTs increased ROS production in cells at cytotoxic concentrations but had no effect at lower concentrations that efficiently inhibit HBV replication. Troponoid-mediated cytotoxicity was significantly decreased upon addition of the ROS scavenger N-acetylcysteine. These studies show that troponoids can increase ROS production at high concentrations within cell lines leading to cytotoxicity, but are not be cytotoxic in primary hepatocytes. Future development of αHTs as potential therapeutics against HBV may need to mitigate ROS production by altering compound design and/or by co-administration with ROS antagonists to ameliorate increased ROS levels.

DOI: https://doi.org/10.1128/AAC.01617-21
ACS Biomater Sci Eng. 2021 Oct 29.

Hafnium Oxide-Based Nanoplatform for Combined Chemoradiotherapy.

Anastasiia A Sherstiuk, Sergey A Tsymbal, Anna F Fakhardo, Vladimir N Morozov, Elena F Krivoshapkina, Evamarie Hey-Hawkins, Pavel V Krivoshapkin.

  Recently, the combined therapy has become one of the main approaches in cancer treatment. Combining different approaches may provide a significant outcome by triggering several death mechanisms or causing increased damage of tumor cells without hurting healthy ones. The supramolecular nanoplatform based on a high-Z metal reported here is a suitable system for the targeted delivery of chemotherapeutic compounds, imaging, and an enhanced radiotherapy outcome. HfO2 nanoparticles coated with oleic acid and a monomethoxypoly(ethylene glycol)-poly(ε-caprolactone) copolymer shell (nanoplatform) are able to accumulate inside cancer cells and release doxorubicin (DOX) under specific conditions. Neither uncoated nor coated nanoparticles show any cytotoxicity in vitro. DOX loaded onto a nanoplatform demonstrates a lower IC50 value than pure DOX. X-ray irradiation of cancer cells loaded with a nanoplatform shows a higher death rate than that for cells without nanoparticles. These results provide an important foundation for the development of complex nanoscale systems for combined cancer treatment.

Keywords:  cancer therapy; coating; combined therapy; drug delivery; hafnium oxide nanoparticles; nanoplatform; radiosensitization; reactive oxygen species

DOI:  https://doi.org/10.1021/acsbiomaterials.1c00973
Mater Sci Eng C Mater Biol Appl. 2021 Nov;pii: S0928-4931(21)00605-6. [Epub ahead of print]130 112465

Near-infrared light-triggered synergistic antitumor therapy based on hollow ZIF-67-derived Co3S4-indocyanine green nanocomplex as a superior reactive oxygen species generator.

Ying Jiang, Yi Lu, Lingli Lei, Shengyu Zhou, Lu Yang, Xiaoyan Yang, Zhigang Xu, Jing Liu, Yingshuai Liu.

  Reactive oxygen species (ROS) with strong oxidability have been considered as effective agents for antitumor therapy through oxidative damage to lipids, proteins, DNA and RNA. In this work, a multifunctional hollow cobaltosic sulfide (Co3S4)/photosensitizer indocyanine green (ICG) nanocomplex (Co3S4-ICG) has been synthesized by efficiently loading ICG into the hollow Co3S4 to realize synergistic antitumor therapy via chemodynamic therapy (CDT), photodynamic therapy (PDT) and photothermal therapy (PTT) under near-infrared (808 nm) laser irradiation. Co3S4 nanoparticles would be degraded in tumor acidic microenvironment into Co2+, which locally triggers a Fenton-like reaction to produce cytotoxic hydroxyl radicals (OH) for CDT. Co3S4-ICG could also produce singlet oxygen (1O2) through a multi-step photochemical process for PDT under 808 nm laser irradiation. The slow release of ICG in the tumor region was achieved due to hollow-structured Co3S4 working as nanocarriers, and which has been proved an effective approach for combined CDT/PDT. In addition, Co3S4-ICG showed high photothermal conversion efficiency (40.5%) for PTT, and excellent OH generation capability via photothermal-improved Fenton reaction, leading to the synergistically improved antitumor efficacy. In vitro and in vivo experimental results confirm that the combined PTT/PDT/photothermal-enhanced CDT therapy can effectively ablate tumors with a negligible systemic toxicity. This work provides a valuable strategy for designing and constructing of a multifunctional nanoplatform for synergistic antitumor therapy of solid tumors.

Keywords:  Fenton-like reaction; Hollow structured Co(3)S(4)-ICG; ROS generator; Synergetic antitumor therapy; Tumor microenvironment-responsive

DOI:  https://doi.org/10.1016/j.msec.2021.112465
Mol Ther Oncolytics. 2021 Dec 17. 23 107-123

Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.

Dan Liu, Xing Jin, Guanzhen Yu, Mingsong Wang, Lei Liu, Wenjuan Zhang, Jia Wu, Fengying Wang, Jing Yang, Qin Luo, Lili Cai, Xi Yang, Xisong Ke, Yi Qu, Zhenye Xu, Lijun Jia, Wen-Lian Chen.

  Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5'-nucleotidase (5'-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5'-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity.

Keywords:  5′-nucleotidase; hypoxanthine-guanine phosphoribosyltransferase; lysosomal degradation; macroautophagy; oleanolic acid; purine salvage pathway; superoxide dismutase 1

DOI:  https://doi.org/10.1016/j.omto.2021.08.013
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01015-4. [Epub ahead of print]111(3S): S56

Mitophagy Induction by ROS-PINK1 Signaling Protects Head and Neck Cancer From Radiotherapy.

Y S Lee, S T Bradley, Z Gurel, K P Nickel, R J Kimple.

PURPOSE/OBJECTIVE(S): Approximate 25% of patients with local advanced head and neck cell carcinoma (HNSCC) treated with radiation still suffer from local relapse and are considered radiation resistant. We previously determined that radiation induces autophagy, a pro-survival cellular stress response, in HNSCC. In this study, we examine the consequence of autophagy inhibition and investigate the molecular mechanism underlying RT-induced autophagy.
MATERIALS/METHODS: Autophagy was assessed using a nano-Luc LC3 reporter assay (Promega), immunoblotting and immunofluorescence for LC3 and acridine orange in multiple HNSCC cell lines. RNAi knockdown of EGFR, LAPTM4B and PINK1 were used to test the involved signaling molecules. CM-H2DCFDA was used as a measure of reactive oxygen species (ROS). Hydrogen peroxide was used to stimulate ROS production. Trolox, a ROS scavenger, was used to determine the correlation between ROS and RT-induced autophagy. Mitophagy determination was completed by using MitoTracker Red (Invitrogen) combined with immunofluorescence staining for LC3 and immunoblotting. Radiation was delivered using a RS225 cabinet irradiator at a dose rate of approximately 3 Gy/min with dose validation by TLD using custom, geometry specific phantoms. SAR405, a VPS34 inhibitor, was used to inhibit autophagy. A flank xenograft model using A253 cells was used to test the combination of autophagy inhibitors and radiotherapy in vivo.
RESULTS: RT caused a two-fold increase in autophagy as assessed using the reporter assay and immunoblotting. Knockdown of EGFR and LAPTM4B, two proteins important in growth-factor deprivation induced autophagy, did not influence autophagy in RT-treated cells. RT did increase the accumulation of ROS (∼50%) and the dephosphorylation of mTOR (∼25%). Addition of Trolox to RT contributed to a considerable decrease in both ROS (∼50%) and autophagy (∼50%). RT also resulted in a mRNA elevation of PINK1 (∼1.6 fold), a mitochondrial modulator. Immunoblotting for LC3 in both the cytoplasmic and mitochondrial fraction indicated RT mostly increases mitophagy rather than bulk autophagy, which was confirmed using immunofluorescent staining for LC3 and MitoTracker red. Using a clonogenic survival assay, the combination of SAR405 and RT resulted in complete loss of cell survival suggesting a radiosensitizing effect. In vivo, SAR405 treatment combined with RT improved tumor control when compared to RT or SAR405 alone.
CONCLUSION: RT-induced mitophagy involves ROS-PINK1 pathway and the regulation of mTOR. Inhibition of autophagy resulted in decreased cell survival in vitro and decreased in vivo tumor growth. These results suggest that targeting mitophagy may be a viable approach to sensitize HNSCC to radiation treatment.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.145
Cell Cycle. 2021 Oct 28. 1-15

YBX1 knockdown induces renal cell carcinoma cell apoptosis via Kindlin-2.

Qiqi Cui, Chao Wang, Shuang Liu, Runxuan Du, Shaoping Tian, Ruibing Chen, Hua Geng, Saravanan Subramanian, Yuanjie Niu, Yong Wang, Dan Yue.

  Among urological tumors, renal cell carcinoma (RCC) is the third-highest mortality rate tumor, and 20%-30% of RCC patients present with metastases at the time of diagnosis. While the treatment of RCC has been improved over the last few years, its mortality stays high. Y-box binding protein 1 (YBX1) is a well-known oncoprotein that has tumor-promoting functions. YBX1 is widely considered to be an attractive therapeutic target in cancer. To develop novel therapeutics to target YBX1, it is of great importance to understand how YBX1 is finely regulated in cancer. Our previous studies showed that YBX1 in RCC cells significantly promoted cell adhesion, migration, and invasion. However, the role of YBX1 in RCC cells apoptosis has not been reported. In this study, we investigated the effect of YBX1 on cell apoptosis and elucidated the mechanisms involved. Results showed that YBX1 regulated RCC cells apoptosis and reactive oxygen species (ROS) generation via Kindlin-2. These findings indicated that YBX1 inhibited RCC cells apoptosis and may serve as a candidate RCC prognostic marker and a potential therapeutic target. Abbreviations: RCC: Renal cell carcinoma; YBX1: Y-box binding protein 1; ROS: Reactive oxygen species; ccRCC: Clear cell renal cell carcinoma; mccRCC: Metastatic clear cell renal cell carcinoma; G3BP1: Ras-GTPase activating protein SH3 domain-binding proteins 1; SPP1: Secreted phosphoprotein 1; NF-κB: Nuclear factor kappa beta; ECM: Extracellular matrix; EMT: Epithelial-mesenchymal transition; PYCR1: Pyrroline-5-carboxylate reductase 1; MEM: Eagle's Minimum Essential Medium; DMEM: Dulbecco's modified Eagle medium; FBS: Fetal bovine serum; PCR: Polymerase chain reaction; shRNA: Short hairpin RNA; siRNA: Small interfering RNA; BSA: Bovine serum albumin; DCFH-DA: 2,7-Dichlorodihydrofluorescein diacetate; FITC: Fluorescein isothiocyanate; PI: Propidium iodide.

Keywords:  Renal cell carcinoma; apoptosis; reactive oxygen species; s-2; y-box binding protein 1

DOI:  https://doi.org/10.1080/15384101.2021.1985771
J Cancer Prev. 2021 Sep 30. 26(3): 195-206

Docosahexaenoic Acid Inhibits Cytokine Expression by Reducing Reactive Oxygen Species in Pancreatic Stellate Cells.

Sun Ah Chung, Joo Weon Lim, Hyeyong Kim.

  Pancreatic stellate cells (PSCs) are activated by inflammatory stimuli, such as TNF-α or viral infection. Activated PSCs play a crucial role in the development of chronic pancreatitis. Polyinosinic-polycytidylic acid (poly (I:C)) is structurally similar to double-stranded RNA and mimics viral infection. Docosahexaenoic acid (DHA) exhibits anti-inflammatory activity. It inhibited fibrotic mediators and reduced NF-κB activity in the pancreas of mice with chronic pancreatitis. The present study aimed to investigate whether DHA could suppress cytokine expression in PSCs isolated from rats. Cells were pre-treated with DHA or the antioxidant N-acetylcysteine (NAC) and stimulated with TNF-α or poly (I:C). Treatment with TNF-α or poly (I:C) increased the expression of monocyte chemoattractant protein 1 (MCP-1) and chemokine C-X3-C motif ligand 1 (CX3CL1), which are known chemoattractants, and enhanced intracellular and mitochondrial reactive oxygen species (ROS) production and NF-κB activity, but reduced mitochondrial membrane potential (MMP). Increased intracellular and mitochondrial ROS accumulation, cytokine expression, MMP disruption, and NF-κB activation were all prevented by DHA in TNF-α- or poly (I:C)-treated PSCs. NAC suppressed TNF-α- or poly (I:C)-induced expression of MCP-1 and CX3CL1. In conclusion, DHA inhibits poly (I:C)- or TNF-α-induced cytokine expression and NF-κB activation by reducing intracellular and mitochondrial ROS in PSCs. Consumption of DHA-rich foods may be beneficial in preventing chronic pancreatitis by inhibiting cytokine expression in PSCs.

Keywords:  Cytokines; Docosahexaenoic acid; Pancreatic stellate cells; Reactive oxygen species

DOI:  https://doi.org/10.15430/JCP.2021.26.3.195
Front Oncol. 2021 ;11 747445

A Novel Ferroptosis-Related 4-Gene Prognostic Signature for Cholangiocarcinoma and Photodynamic Therapy.

Zi-Jian Zhang, Yun-Peng Huang, Xiao-Xue Li, Zhong-Tao Liu, Kai Liu, Xiao-Feng Deng, Li Xiong, Heng Zou, Yu Wen.

  Cholangiocarcinoma is the second most common malignant tumor in the hepatobiliary system. Compared with data on hepatocellular carcinoma, fewer public data and prognostic-related studies on cholangiocarcinoma are available, and effective prognostic prediction methods for cholangiocarcinoma are lacking. In recent years, ferroptosis has become an important subject of tumor research. Some studies have indicated that ferroptosis plays an important role in hepatobiliary cancers. However, the prediction of the prognostic effect of ferroptosis in patients with cholangiocarcinoma has not been reported. In addition, many reports have described the ability of photodynamic therapy (PDT), a potential therapy for cholangiocarcinoma, to regulate ferroptosis by generating reactive oxygen species (ROS). By constructing ferroptosis scores, the prognoses of patients with cholangiocarcinoma can be effectively predicted, and potential gene targets can be discovered to further enhance the efficacy of PDT. In this study, gene expression profiles and clinical information (TCGA, E-MTAB-6389, and GSE107943) of patients with cholangiocarcinoma were collected and divided into training sets and validation sets. Then, a model of the ferroptosis gene signature was constructed using least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. Furthermore, through the analysis of RNA-seq data after PDT treatment of cholangiocarcinoma, PDT-sensitive genes were obtained and verified by immunohistochemistry staining and Western blot. The results of this study provide new insight for predicting the prognosis of cholangiocarcinoma and screening target genes that enhance the efficacy of PDT.

Keywords:  ROS - reactive oxygen species; cholangiocarcinoma; ferroptosis; photodynamic therapy; prognosis

DOI:  https://doi.org/10.3389/fonc.2021.747445
J Nanobiotechnology. 2021 Oct 26. 19(1): 340

Understanding of catalytic ROS generation from defect-rich graphene quantum-dots for therapeutic effects in tumor microenvironment.

Xichu Wang, Chuangang Hu, Zi Gu, Liming Dai.

  Owing to their low cost, high catalytic efficiency and biocompatibility, carbon-based metal-free catalysts (C-MFCs) have attracted intense interest for various applications, ranging from energy through environmental to biomedical technologies. While considerable effort and progress have been made in mechanistic understanding of C-MFCs for non-biomedical applications, their catalytic mechanism for therapeutic effects has rarely been investigated. In this study, defect-rich graphene quantum dots (GQDs) were developed as C-MFCs for efficient ROS generation, specifically in the H2O2-rich tumor microenvironment to cause multi-level damages of subcellular components (even in nuclei). While a desirable anti-cancer performance was achieved, the catalytic performance was found to strongly depend on the defect density. It is for the first time that the defect-induced catalytic generation of ROS by C-MFCs in the tumor microenvironment was demonstrated and the associated catalytic mechanism was elucidated. This work opens a new avenue for the development of safe and efficient catalytic nanomedicine.

Keywords:  Carbon-based metal-free catalyst; Defect; Graphene quantum dot; Reactive oxygen species; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12951-021-01053-6
Antioxid Redox Signal. 2021 Oct 29.

Lung tumor growth promotion by tobacco-specific nitrosamines involves the β2-adrenergic receptors-dependent stimulation of mitochondrial REDOX signaling.

Saharnaz Sarlak, Claude Lalou, Ana Carolina Bastos Sant'Anna-Silva, Walid Mahfouf, Monica De Luise, Benoît Rousseau, Julien Izotte, Stephane Claverol, Didier Lacombe, Efterpi Nikitopoulou, Ming Yang, Marcus Oliveira, Christian Frezza, Guiseppe Gasparre, Hamid Reza Rezvani, Nivea Dias Amoedo, Rodrigue Rossignol.

AIMS: Lung cancer is the leading cause of cancer death worldwide, and tobacco smoking is a recognized major risk factor for lung tumor development. We analyzed the effect of tobacco-specific nitrosamines (TSNAs) on human lung adenocarcinoma metabolic reprogramming, an emergent hallmark of carcinogenesis.
RESULTS: A series of in vitro and in vivo bioenergetic, proteomic, metabolomic and tumor biology studies were performed to analyze changes in lung cancer cell metabolism and the consequences for hallmarks of cancer, including tumor growth, cancer cell invasion and redox signaling. The findings revealed that nitrosamine ketone (NNK) stimulates mitochondrial function and promotes lung tumor growth in vivo. These malignant properties were acquired from the induction of mitochondrial biogenesis induced by the upregulation and activation of the beta-adrenergic receptor (β2-AR)-nicotinic acetylcholine receptor subunit alpha-7 (CHRNAα7)-dependent nitrosamine canonical signaling pathway. The observed NNK metabolic effects were mediated by TFAM overexpression and revealed a key role for mitochondrial reactive oxygen species (mtROS) and Annexin A1 in tumor growth promotion. Conversely, ectopic expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) rescued the reprogramming and malignant metabolic effects of exposure to NNK and overexpression of TFAM, underlining the link between NNK and mitochondrial redox signaling in lung cancer.
INNOVATION: Our findings describe the metabolic changes caused by NNK in a mechanistic framework for understanding how cigarette smoking causes lung cancer.
CONCLUSION: Mitochondria play a role in the promotion of lung cancer induced by tobacco-specific nitrosamines.

DOI: https://doi.org/10.1089/ars.2020.8259
Onco Targets Ther. 2021 ;14 5097-5106

Serum Reactive Oxygen Species Modulator 1 as a Novel Predictive Biomarker for Resected Lung Adenocarcinoma: A Retrospective Pilot Study.

Boksoon Chang, In Kyung Hwang, Seung Hyeun Lee.

   Purpose: Reactive oxygen species modulator 1 (Romo1) is a key regulator of intracellular reactive oxygen species production. Previous studies have shown that Romo1 overexpression in tumor tissue is associated with poor clinical outcomes in various clinical settings for lung cancer treatment. The aim of the present study was to assess the predictive value of serum Romo1 in patients received curative resection for lung cancer.
Methods: Serum samples were collected from patients with lung adenocarcinoma who underwent surgical resection. Baseline serum Romo1 and carcinoembryonic antigen (CEA) levels before surgery were measured. Univariate and multivariate analyses were performed to identify whether serum Romo1 was associated with disease-free survival (DFS).
Results: A total of 77 samples were analyzed. Using the cut-off value of 866 pg/mL, the population was classified into low (n = 42, 54.4%) and high (n = 35, 45.4%) Romo1 groups. The median DFS of the high Romo1 group was significantly shorter than that of the low Romo1 group (25.5 months vs not reached [NR], p = 0.0105). In addition, the median DFS of patients in the high CEA (>2.9 ng/mL) group was significantly shorter than those in the low CEA group (26.8 months vs NR, p = 0.0092). Multivariate analyses showed that both high Romo1 and CEA levels were independently associated with poor DFS (hazard ratio [HR] = 2.19; 95% confidence interval [CI]: 1.14-8.37, and HR = 2.95; 95% CI: 1.23-9.21, respectively). Moreover, combination of these two biomarkers resulted in higher HR of 4.11 (95% CI, 1.53-14.05) for DFS than those of Romo1 and CEA.
Conclusion: Elevated serum Romo1 levels were significantly associated with early recurrence in patients with lung adenocarcinoma treated with surgical resection. Serum Romo1 may be a promising predictive biomarker for this patient population.

Keywords:  biomarker; reactive oxygen species modulator 1; recurrence; serum; surgery

DOI:  https://doi.org/10.2147/OTT.S336399
Rev Med Virol. 2021 Oct 25. e2308

Nuclear factor erythroid 2-related factor 2 in human papillomavirus-related cancers.

Alfredo Cruz-Gregorio, Ana Karina Aranda-Rivera, José Pedraza-Chaverri.

  High-risk human papillomavirus (HR-HPV) infection is a necessary cause for the development of cervical cancer. Moreover, HR-HPV is also associated with cancers in the anus, vagina, vulva, penis and oropharynx. HR-HPVs target and modify the function of different cell biomolecules, such as glucose, amino acids, lipids and transcription factors (TF), such as p53, nuclear factor erythroid 2-related factor 2 (Nrf2), among others. The latter is a master TF that maintains redox homeostasis. Nrf2 also induces the transcription of genes associated with cell detoxification. Since both processes are critical for cell physiology, Nrf2 deregulation is associated with cancer development. Nrf2 is a crucial molecule in HPV-related cancer development but underexplored. Moreover, Nrf2 activation is also associated with resistance to chemotherapy and radiotherapy in these cancers. This review focusses on the importance of Nrf2 during HPV-related cancer development, resistance to therapy and potential therapies associated with Nrf2 as a molecular target.

Keywords:  HPV-related cancers; Keap 1; Nrf2; antioxidants; oxidative stress; redox state

DOI:  https://doi.org/10.1002/rmv.2308
ChemMedChem. 2021 Oct 28.

An antiinflammatory Fe3O4-porphyrin nanohybrid capable of apoptosis through upregulation of p21 kinase inhibitor having immunoprotective properties under anti-cancer PDT conditions.

Devashish Sengupta, Subhojit Das, Debdulal Sharma, Saran Chattopadhyaya, Avinaba Mukherjee, Zeaul Hoque Mazumdar, Biswajit Das, Samita Basu, Mahuya Sengupta.

  We report the influence of Fe 3 O 4 nanoparticles (NPs) on porphyrins in the development of photosensitisers (PSs) for efficient photodynamic therapy (PDT) and possible post-PDT responses for inflicting cancer cell death. Except for Au, most metal-based nanomaterials disqualify clinical applications. The FDA and other competent agencies have approved Feraheme and a few other iron oxide NPs for clinical use, paving the way for novel biocompatible immunoprotective superparamagnetic iron oxide nanohybrids to be developed as nanotherapeutics. A water-soluble, nanohybrid E-NP comprising superparamagnetic Fe 3 O 4 NPs functionalised with tri-pyridyl porphyrin PS was introduced through a rigid 4-carboxyphenyl linker. As a PDT agent, the efficacy of E-NP towards the AGS cancer cell line showed enhanced photosensitising ability as determined through in vitro photobiological assays. The cellular uptake of E-NPs in the AGS cell line led to apoptosis by upregulating ROS through cell cycle arrest and loss in mitochondrial membrane potential. The subcellular localisation of the PSs in the cell mitochondria stimulated apoptosis through the up-regulation of p21, a proliferation inhibitor capable of preventing tumour development. Under both PDT and non-PDT conditions, this nanohybrid can act as an anti-inflammatory agent by reducing the production of NO and superoxide ions in murine macrophages, thus minimising collateral damage to healthy cells.

Keywords:  Nitric oxide release and Superoxide ions downregulation; Photodynamic therapy (PDT)-induced apoptosis; Superparamagnetic Fe3O4-Porphyirn nanohybrids; macrophages; p21 Kinase Inhibitor

DOI:  https://doi.org/10.1002/cmdc.202100550
Oxid Med Cell Longev. 2021 ;2021 5620475

THAP9-AS1 Promotes Tumorigenesis and Reduces ROS Generation through the JAK2/STAT3 Signaling Pathway by Increasing SOCS3 Promoter Methylation in Osteosarcoma.

Shuai Yang, Bing Wang, Chang Liu, Qizun Wang, Ronghuan Wang, Weiliang Su, Youfu Zhu, Maohua Li, Zhaoyang Guo, Xiaolin Wu, Feng Chen.

Increasing studies have demonstrated that dysfunction of long noncoding RNAs (lncRNAs) plays critical roles in the development of human cancers. THAP9-AS1 has been reported to be dysregulated and associated with tumor progression in some cancers. However, the function and mechanism of THAP9-AS1 in osteosarcoma (OS) remain unclear. In the present study, we found that the expression of THAP9-AS1 was significantly upregulated in OS tissues and associated with the advanced stage of tumors and poor prognosis of patients. Blast comparison results showed that the SOCS3 promoter region and THAP9-AS1 had base complementary pairing binding sites. The interactions between THAP9-AS1, DNA methyltransferases (DNMTs), and SOCS3 were assessed by RIP and ChIP assays. The results of methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) validated that THAP9-AS1 enhanced the methylation level of the SOCS3 promoter. The mRNA levels of SOCS3 in OS cells could be reversed by the demethylation agent 5-aza-2'-deoxycytidine. The mRNA expression of SOCS3 was downregulated in OS tissues and negatively correlated with THAP9-AS1 expression in tumors. Moreover, the western blot and immunofluorescence (IF) assay data showed that THAP9-AS1 activated the JAK2/STAT3 signaling pathway by upregulating p-JAK2 and p-STAT3 and the nuclear translocation of p-STAT3. Functionally, ectopic expression of THAP9-AS1 promoted cell proliferation, migration, and invasion and inhibited apoptosis, and this phenomenon could be reversed by SOCS3. Introduction of the JAK/STAT inhibitor AG490 partially abolished the stimulative effect of THAP9-AS1 on cellular processes. In addition, THAP9-AS1 decreased oxidative stress by reducing reactive oxygen species (ROS) and enhancing the mitochondrial membrane potential of OS cells via the SOCS3/JAK2/STAT3 pathway. Stable overexpression of THAP9-AS1 contributed to tumor growth and metastasis in vivo. In total, our findings suggested that upregulation of THAP9-AS1 might recruit DNMTs to epigenetically inhibit SOCS3, thereby activating the JAK2/STAT3 signaling pathway and oncogenesis of OS. These results provide novel insights for the understanding of OS progression.

DOI: https://doi.org/10.1155/2021/5620475