bims-rehoca 2021-11-07 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–11–07
twenty papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

A polymer‑calcium phosphate nanocapsule for RNAi-induced oxidative stress and cascaded chemotherapy.
Iron-Dependent Autophagic Cell Death Induced by Radiation in MDA-MB-231 Breast Cancer Cells.
Eriocitrin, a dietary flavonoid suppressed cell proliferation, induced apoptosis through modulation of JAK2/STAT3 and JNK/p38 MAPKs signaling pathway in MCF-7 cells.
New Cu(II) coordination polymer inhibits cervical cancer development by regulating BRCA1 protein via miR-9-5p.
Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy.
Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/β-catenin signaling pathway in HeLa cells.
An NIR-II Responsive Nanoplatform for Cancer Photothermal and Oxidative Stress Therapy.
8-Formylophiopogonanone B induces ROS-mediated apoptosis in nasopharyngeal carcinoma CNE-1 cells.
A modular ROS-responsive platform co-delivered by 10-hydroxycamptothecin and dexamethasone for cancer treatment.
Redox sensitive miR-27a/b/Nrf2 signaling in Cr(VI)-induced carcinogenesis.
MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer.
NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.
Novel mechanisms in alcohol neurodevelopmental disorders via BRCA1 depletion and BRCA1-dependent NADPH oxidase regulation.
Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells.
Diazaborines Are a Versatile Platform to Develop ROS-Responsive Antibody Drug Conjugates*.
High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy.
Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.
Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.
In Vitro Cytotoxicity and Oxidative Stress Evaluation of Valerian (Valeriana officinalis) Methanolic Extract in Hepg2 and Caco2 Cells
Self-Delivery Nanomedicine for Glutamine-Starvation Enhanced Photodynamic Tumor Therapy.

J Control Release. 2021 Nov 02. pii: S0168-3659(21)00583-6. [Epub ahead of print]

A polymer‑calcium phosphate nanocapsule for RNAi-induced oxidative stress and cascaded chemotherapy.

Jinsheng Huang, Chujie Zheng, Hong Xiao, Huiling Huang, Yiyao Wang, Minzhao Lin, Jun Pang, Yong Wang, Yuanyuan Yuan, Xintao Shuai.

  As most of intracellular reactive oxygen species (ROS) is produced in the mitochondria, mitochondrial modulation of cancer cell is a promising strategy for maximizing the in situ-activable combination therapy of oxidative catastrophe and cascaded chemotherapy. Herein, a serum-stable polymer‑calcium phosphate (CaP) hybrid nanocapsule carrying siRNA against ADP-ribosylation factor 6 (Arf6) overexpressed in cancer cells and parent drug camptothecin (CPT), designated as PTkCPT/siRNA, was developed for the RNAi-induced oxidative catastrophe and cascaded chemotherapy. A copolymer of mPEG-P(Asp-co-TkCPT), covalently tethered with chemotherapeutic CPT via a ROS-labile dithioketal (Tk) linker, was synthesized and self-assembled into a PTkCPT micelle as a nanotemplate for the CaP mineralization. The as-prepared PTkCPT/siRNA nanoparticle showed a core-shell-distinct nanocapsule which was consisted of a spherical polymeric core enclosed within a CaP shell capable of releasing siRNA in response to lysosomal acidity. Blocking Arf6 signal pathway of cancer cells led to their mitochondrial aggregation and subsequently induced a burst of ROS for oxidative catastrophe, which further triggered the cascaded CPT chemotherapy via the breakage of ROS-labile dithioketal linker. This strategy of RNAi-induced oxidative catastrophe and cascaded chemotherapy resulted in a significant combination effect on cancer cell killing and tumor growth inhibition in mice with low side effects, and provided a promising paradigm for precise cancer therapy.

Keywords:  Cascaded treatment; Chemotherapy; Mitochondrial modulation; Oxidative stress; Polymer prodrug; siRNA delivery

DOI:  https://doi.org/10.1016/j.jconrel.2021.10.030
Front Cell Dev Biol. 2021 ;9 723801

Iron-Dependent Autophagic Cell Death Induced by Radiation in MDA-MB-231 Breast Cancer Cells.

Shumei Ma, Xinxin Fu, Lin Liu, Yi Liu, Hao Feng, Heya Jiang, Xiaomei Liu, Rui Liu, Zhenzhen Liang, Mengke Li, Zhujun Tian, Boqi Hu, Yongheng Bai, Bing Liang, Xiaodong Liu.

  In radiation oncology, ionizing radiation is used to kill cancer cells, in other words, the induction of different types of cell death. To investigate this cellular death and the associated iron accumulation, the transfer, release, and participation of iron after radiation treatment was analyzed. We found that radiation-induced cell death varied in different breast cancer cells and autophagy was induced in MDA-MB-231 and BT549 cells (triple negative breast cancer cell line) rather than in MCF-7 and zr-75 cells. Iron chelator deferoxamine (DFO), the autophagy inhibitor 3MA, silencing of the autophagy-related genes ATG5, and Beclin 1 could decrease radiation induced cell death in MDA-MB-231 cells, while inhibitors of apoptosis such as Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1 (Fer-1), and necroptosis inhibitor Necrostatin-1 showed no change. This suggests the occurrence of autophagic cell death. Furthermore, we found that iron accumulation and iron regulatory proteins, including transferrin (Tf), transferrin receptor (CD71), and Ferritin (FTH), increased after radiation treatment, and the silencing of transferrin decreased radiation-induced cell death. In addition, radiation increased lysosomal membrane permeabilization (LMP) and the release of lysosomal iron and cathepsins, while cathepsins silencing failed to change cell viability. Radiation-induced iron accumulation increased Reactive oxygen species (ROS) generation via the Fenton reaction and increased autophagy in a time-dependent manner. DFO, N-acetylcysteine (NAC), and overexpression of superoxide dismutase 2 (SOD2) decreased ROS generation, autophagy, and cell death. To summarize, for the first time, we found that radiation-induced autophagic cell death was iron-dependent in breast cancer MDA-MB-231 cells. These results provide new insights into the cell death process of cancers and might conduce to the development and application of novel therapeutic strategies for patients with apoptosis-resistant breast cancer.

Keywords:  autophagy; breast cancer; iron; lysosome membrane permeabilization (LMP); radiation; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3389/fcell.2021.723801
J Biochem Mol Toxicol. 2021 Nov 01. e22943

Eriocitrin, a dietary flavonoid suppressed cell proliferation, induced apoptosis through modulation of JAK2/STAT3 and JNK/p38 MAPKs signaling pathway in MCF-7 cells.

Chengliang Yuan, Guoping Chen, Chengbao Jing, Mengxue Liu, Bo Liang, Guojin Gong, Mei Yu.

  Eriocitrin, a lemons flavanone, exhibits several biological properties, antiproliferative, and proapoptotic effects. However, its molecular mechanical action is not entirely clarified. Oxidative stress causes abnormal stimulation of signal transducer and activator of transcription 3 (STAT3) and c-Jun NH2-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs) signaling has been strongly connected with the ruling of cell survival and apoptosis of cancer cells. Herein, we investigated an antiproliferative and proapoptotic effect that Eriocitrin modulates STAT3/MAPKs signaling activation in MCF-7 cells. We noticed that Eriocitrin strongly enhances reactive oxygen species (ROS) generation, alteration of mitochondrial outer membrane potential, and enhances apoptotic morphological changes. Furthermore, Eriocitrin suppressed STAT3 phosphorylation via inhibiting an upstream molecule of JAK2 and Src kinase activation, thereby blocking STAT3 nuclear translocation. Similarly, Eriocitrin causes oxidative stress-mediated JNK/p38 MAPK signaling activation. We confirmed that Eriocitrin induced ROS-mediated apoptosis inhibited by the antioxidant substance of N-acetylcysteine. Eriocitrin induced apoptosis via suppression of STAT3 signaling regulated proteins, activating proapoptotic factors Bax, caspase 7, 8, 9 and suppressing Bcl-2, Bcl-x expression in MCF-7 cells. Overall, these results evidenced that Eriocitrin can affect multiple signaling events associated with tumorigenesis. From this evidence, Eriocitrin, a novel chemotherapeutic agent, can be used to treat breast cancer.

Keywords:  Eriocitrin; STAT3/MAPKs; apoptosis; cell proliferation; oxidative stress

DOI:  https://doi.org/10.1002/jbt.22943
J Inorg Biochem. 2021 Oct 28. pii: S0162-0134(21)00302-0. [Epub ahead of print]226 111655

New Cu(II) coordination polymer inhibits cervical cancer development by regulating BRCA1 protein via miR-9-5p.

Lin Zhang, Wei-Ping Li.

  A novel Cu(II)-based coordination polymer [chemical composition, {[CuL(CH3CO2)](H2O)(DMF)}n (1, DMF = N,N-dimethylformamide) was successfully prepared via Cu(NO3)2·3H2O reaction with HL ligand in DMF and H2O mixture by using a hetero-donor ligand 4-(bis(4-(4H-1,2,4-triazol-4-yl)phenyl)amino)benzoic acid (HL) featuring carboxylic acid and triazole groups. Reverse transcription-polymerase chain reaction (RT-PCR) was adopted to determine miR-9-5p expression in cervical cancer cells after compound treatment. Bioinformatic analysis and luciferase reporter assay were utilized to confirm miR-9-5p and BRCA1 interaction to discover the potential goal of miR-9-5p in cervical cancer cells. Cell Counting Kit-8 (CCK-8) and reactive oxygen species (ROS) detection kits were adopted to examine cancer cell proliferation and ROS accumulation after compound treatment.

Keywords:  BRCA1; Cervical cancer; Cu complex; Proliferation; ROS; miR-9-5p

DOI:  https://doi.org/10.1016/j.jinorgbio.2021.111655
Acta Pharm Sin B. 2021 Oct;11(10): 3231-3243

Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy.

Yu Liang, Li Zhang, Chao Peng, Shiyu Zhang, Siwen Chen, Xin Qian, Wanxian Luo, Qing Dan, Yongyan Ren, Yingjia Li, Bingxia Zhao.

  Ferroptosis, as a newly discovered cell death form, has become an attractive target for precision cancer therapy. Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione (GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). However, the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported. Herein, novel tumor microenvironments (TME)-activated metal-organic frameworks involving Fe & Cu ions bridged by disulfide bonds with PEGylation (FCSP MOFs) were developed, which would be degraded specifically under the redox TME, simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction, therefore causing ferroptosis. More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs. The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy. Better tumor therapeutic efficiency could be achieved by doxorubicin (DOX) loading since it can not only cause apoptosis, but also indirectly produce H2O2 to amplify Fenton reaction. Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays.

Keywords:  Drug delivery; Fenton reaction; Ferroptosis; GSH depletion; Metal-organic frameworks (MOFs); Tumor microenvironments

DOI:  https://doi.org/10.1016/j.apsb.2021.01.016
J Biochem Mol Toxicol. 2021 Nov 03. e22944

Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/β-catenin signaling pathway in HeLa cells.

Huanan Kang, Yiming Sun, Xijiao Hu, Li Liu.

  Cervical cancer is one of the leading malignant cancers that is the fourth prominent cause of malignancy-related mortality in women globally. There is a predominant validation to a beneficial target in Wnt/β-catenin signaling in cervical carcinogenesis as they are very much deregulated in cancer. Previous studies reported Gigantol (GG) showed suppressive properties on the Wnt/β-catenin pathway in other tumor cells, but no evidence is available regarding GG suppressing Wnt/β-catenin signaling cervical tumor cells. Hence, the current research was planned to examine the suppressive effects of GG on HeLa cells and investigate the mechanism of action. HeLa cells were treated by GG in various doses and then appraising cell viability, oxidant/antioxidant levels, ∆ѰM status, reactive oxygen species (ROS) generation, apoptosis, and cell proliferation via Wnt/β-catenin signaling. We observed that GG noticeably inhibits cell proliferation, increased ROS generation, lipid peroxidation, mitochondrial membrane depolarization (∆ѰM), and increased apoptotic morphological changes of nuclear fragmentation and condensation. Moreover, GG effectively enhances proapoptotic, decreased ∆ѰM and antioxidant amounts, and mitigated Wnt/β-catenin signaling. Concisely, these findings proved that activating apoptosis and suppression of cell proliferation in GG treated HeLa cells was documented by the alleviation of Wnt/β-catenin signaling. Therefore, this study suggested that GG might develop a therapeutic effect against cervical carcinogenesis.

Keywords:  Gigantol; HeLa cells; Wnt/β-catenin signaling; apoptosis; cervical cancer

DOI:  https://doi.org/10.1002/jbt.22944
Front Bioeng Biotechnol. 2021 ;9 751757

An NIR-II Responsive Nanoplatform for Cancer Photothermal and Oxidative Stress Therapy.

Bin Huang, Yuanpeng Huang, Han Han, Qiuyue Ge, Dongliang Yang, Yanling Hu, Meng Ding, Yanqing Su, Yanbin He, Jinjun Shao, Jianfeng Chu.

  Chemodynamic therapy as an emerging therapeutic strategy has been implemented for oncotherapy. However, the reactive oxygen species can be counteracted by the exorbitant glutathione (GSH) produced by the tumor cells before exerting the antitumor effect. Herein, borneol (NB) serving as a monoterpenoid sensitizer, and copper sulfide (CuS NPs) as an NIR-II photothermal agent were loaded in a thermo-responsive vehicle (NB/CuS@PCM NPs). Under 1,060-nm laser irradiation, the hyperthermia produced by CuS NPs can be used for photothermal therapy and melt the phase change material for drug delivery. In the acidity microenvironment, the CuS NPs released from NB/CuS@PCM NPs could degrade to Cu2+, then Cu2+ was reduced to Cu+ during the depletion of GSH. As Fenton-like catalyst, the copper ion could convert hydrogen peroxide into hydroxyl radicals for chemodynamic therapy. Moreover, the NB originated from NB/CuS@PCM NPs could increase the intracellular ROS content to improve the treatment outcome of chemodynamic therapy. The animal experimental results indicated that the NB/CuS@PCM NPs could accumulate at the tumor site and exhibit an excellent antitumor effect. This work confirmed that the combination of oxidative stress-induced damage and photothermal therapy is a potential therapeutic strategy for cancer treatment.

Keywords:  chemodynamic therapy; drug delivery; phase change material; photothermal ablation therapy; responsive nanomaterial

DOI:  https://doi.org/10.3389/fbioe.2021.751757
Toxicol Res (Camb). 2021 Oct;10(5): 1052-1063

8-Formylophiopogonanone B induces ROS-mediated apoptosis in nasopharyngeal carcinoma CNE-1 cells.

Ya-Jing Zhang, Zhen-Lin Mu, Ping Deng, Yi-Dan Liang, Li-Chuan Wu, Ling-Ling Yang, Zhou Zhou, Zheng-Ping Yu.

  Cancer is one of the leading causes of death in the world. It is very important to find drugs with high efficiency, low toxicity, and low side effects for the treatment of cancer. Flavonoids and their derivatives with broad biological functions have been recognized as anti-tumor chemicals. 8-Formylophiopogonanone B (8-FOB), a naturally existed homoisoflavonoids with rarely known biological functions, needs pharmacological evaluation. In order to explore the possible anti-tumor action of 8-FOB, we used six types of tumor cells to evaluate in vitro effects of this agent on cell viability and tested the effects on clone formation ability, scratching wound-healing, and apoptosis. In an attempt to elucidate the mechanism of pharmacological action, we examined 8-FOB-induced intracellular oxidative stress and -disrupted mitochondrial function. Results suggested that 8-FOB could suppress tumor cell viability, inhibit cell migration and invasion, induce apoptosis, and elicit intracellular ROS production. Among these six types of tumor cells, the nasopharyngeal carcinoma CNE-1 cells were the most sensitive cancer cells to 8-FOB treatment. Intracellular ROS production played a pivotal role in the anti-tumor action of 8-FOB. Our present study is the first to document that 8-FOB has anti-tumor activity in vitro and increases intracellular ROS production, which might be responsible for its anti-tumor action. The anti-tumor pharmacological effect of 8-FOB is worthy of further investigation.

Keywords:  8-formylophiopogonanone B; anti-tumor; apoptosis; cisplatin; oxidative stress

DOI:  https://doi.org/10.1093/toxres/tfab087
J Control Release. 2021 Oct 28. pii: S0168-3659(21)00581-2. [Epub ahead of print]340 102-113

A modular ROS-responsive platform co-delivered by 10-hydroxycamptothecin and dexamethasone for cancer treatment.

Qingye Meng, Hao Hu, Xiaodong Jing, Ying Sun, Liping Zhou, Yaowei Zhu, Bing Yu, Hailin Cong, Youqing Shen.

  Traditional and single treatment strategies are difficult to achieve good results due to tumor resistance and complex mechanisms. Combination therapy through co-delivery systems is one of the methods to improve the effectiveness of cancer treatment. The polyprodrug platform has inherent advantages such as high drug loading and strong stability. Herein, a new reactive oxygen species (ROS)-responsive micelle composed of poly 10-hydroxycamptothecin (pHCPT) and PEG is reported, which loaded dexamethasone (DEX) as synergistic drugs. The micelles collapse in the complex microenvironment of tumor cells to release DEX. The first released DEX can increase the ROS level of tumor cells, thereby facilitating the cleavage of thioketal bonds to release intact HCPT molecules. Meanwhile, DEX can normalize tumor blood vessels, reduce adverse reactions, and further improve the efficacy of HCPT. This co-delivery system shows an ideal tumor suppressive effect in vivo and in vitro. Designing drugs into a modular multi-drug platform and selecting appropriate synergistic drugs according to the treatment plan provides a convenient strategy for future clinical treatment.

Keywords:  Chemotherapy; Co-delivery system; Polyprodrug; ROS-responsive; Synergistic treatment

DOI:  https://doi.org/10.1016/j.jconrel.2021.10.027
Sci Total Environ. 2021 Oct 27. pii: S0048-9697(21)06196-9. [Epub ahead of print] 151118

Redox sensitive miR-27a/b/Nrf2 signaling in Cr(VI)-induced carcinogenesis.

Lin Wang, Khaliunaa Bayanbold, Lei Zhao, Yifang Wang, Andrea Adamcakova-Dodd, Peter S Thorne, Hushan Yang, Bing-Hua Jiang, Ling-Zhi Liu.

  Hexavalent chromium [Cr(VI)] is a well-known carcinogen that can cause several types of cancer including lung cancer. NF-E2-related factor 2 (Nrf2), the redox sensitive transcription factor, can protect normal cells from a variety of toxicants and carcinogens by inducing the expression of cellular protective genes and maintaining redox balance. However, Nrf2 also protects cancer cells from radio- and chemo-therapies and facilitates cancer progression. Although Cr(VI) treatment has been demonstrated to upregulate Nrf2 expression, the mechanisms for Nrf2 regulation upon chronic Cr(VI) exposure remain to be elucidated. We found that Nrf2 was upregulated in BEAS-2B cells exposed to Cr(VI) from 1 to 5 months, and also in Cr(VI)-induced transformed (Cr-T) cells with Cr(VI) treatment for 6 months. We showed that KEAP1, the classic negative regulator of Nrf2, was downregulated after Cr(VI) exposure for 4 months, suggesting that Nrf2 induction by Cr(VI) treatment is through KEAP1 decrease at late stage. To further decipher the mechanisms of Nrf2 upregulation at early stage of Cr(VI) exposure, we demonstrated that miR-27a and miR-27b were redox sensitive miRNAs, since reactive oxygen species (ROS) scavengers induced miR-27a/b expression. After Cr(VI) exposure for 1 month, the expression levels of miR-27a/b was dramatically decreased. The changes of miR-27a/b and their target Nrf2 were confirmed in vivo by mouse model intranasally exposed to Cr(VI) for 12 weeks. Nrf2 was a direct target of miR-27a/b, which acted as tumor suppressors in vitro and in vivo to inhibit tumorigenesis and cancer development of Cr-T cells. The results suggested that the inhibition of miR-27a/b was responsible for Nrf2 upregulation at both early stage and late stage of Cr(VI) exposure. This novel regulation of Nrf2 upon chronic Cr(VI) exposure through redox-regulated miR-27a/b will provide potential targets for preventing and treating Cr(VI)-induced carcinogenesis in the future.

Keywords:  Chromium (VI); Lung cancer; Nrf2; Tumor growth; miR-27a/b

DOI:  https://doi.org/10.1016/j.scitotenv.2021.151118
Mol Carcinog. 2021 Nov 02.

MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer.

Liurong Liu, Huihui Yao, Xin Zhou, Junjie Chen, Guoliang Chen, Xinyu Shi, Guanting Wu, Guoqiang Zhou, Songbing He.

  Colorectal cancer (CRC) is the second most common cancer-related deaths throughout the world. Ferroptosis is a recently regulated form of cell death, lately gains attention. MicroRNA-15a-3p (miR-15a-3p) plays a regulatory role in various kinds of cancers. However, the role of miR-15a-3p in cellular ferroptosis is still unclear. Here, we aimed to clarify whether miR-15a-3p could regulate the ferroptosis of CRC. Here we identified miR-15a-3p positively regulates ferroptosis via directly targeting glutathione peroxidase glutathione peroxidase 4 (GPX4) in CRC. Overexpression of miR-15a-3p repressed GPX4 through binding to the 3'-untranslated region of GPX4, resulting in increased reactive oxygen species level, intracellular Fe2+ level, and malondialdehyde accumulation in vitro and in vivo. Correspondingly, suppression of miR-15a-3p reduced the sensitivity of CRC cells to erastin and GPX4. Taken together, these data demonstrate that miR-15a-3p regulates ferroptosis through targeting GPX4 in CRC cells, illustrating the novel role of microRNA in ferroptosis.

Keywords:  GPX4; colorectal cancer; ferroptosis; miR-15a-3p

DOI:  https://doi.org/10.1002/mc.23367
BMC Cancer. 2021 Nov 05. 21(1): 1181

NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.

Xiangsheng Su, Yihang Yang, Qing Yang, Bo Pang, Shicheng Sun, Yanjun Wang, Qiujiang Qiao, Changfa Guo, Huanting Liu, Qi Pang.

   BACKGROUND: Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear.
METHODS: The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo.
RESULTS: The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo.
CONCLUSION: Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.

Keywords:  Aerobic glycolysis; FOXM1; Glioblastoma; NOX4; ROS

DOI:  https://doi.org/10.1186/s12885-021-08933-y
Redox Biol. 2021 Sep 23. pii: S2213-2317(21)00308-6. [Epub ahead of print]48 102148

Novel mechanisms in alcohol neurodevelopmental disorders via BRCA1 depletion and BRCA1-dependent NADPH oxidase regulation.

Danielle M Drake, Peter G Wells.

  The breast cancer 1 protein (BRCA1) facilitates DNA repair, preventing embryolethality and protecting the fetus from reactive oxygen species (ROS)-induced developmental disorders mediated by oxidatively damaged DNA. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), characterized by aberrant behaviour and enhanced ROS formation and proteasomal protein degradation. Herein, ROS-producing NADPH oxidase (NOX) activity was higher in Brca1 +/- vs. +/+ fetal and adult brains, and further enhanced by a single EtOH exposure. EtOH also enhanced catalase and proteasomal activities, while conversely reducing BRCA1 protein levels without affecting Brca1 gene expression. EtOH-initiated adaptive postnatal freezing behaviour was lost in Brca1 +/- progeny. Pretreatment with the free radical spin trap and ROS inhibitor phenylbutylnitrone blocked all EtOH effects, suggesting ROS-dependent mechanisms. This is the first in vivo evidence of NOX regulation by BRCA1, and of EtOH-induced, ROS-mediated depletion of BRCA1, revealing novel mechanisms of BRCA1 protection in FASD.

Keywords:  Breast cancer 1 susceptibility gene (Brca1); Catalase; Fear conditioning; NADPH oxidase (NOX); Neurodevelopmental disorders; Proteasomal activity

DOI:  https://doi.org/10.1016/j.redox.2021.102148
Cancer Biol Ther. 2021 Oct 31. 1-8

Biguanide drugs enhance cytotoxic effects of cisplatin by depleting aspartate and NAD+ in sensitive cancer cells.

Ellen Tully, Santosh Bharti, Juhyung Woo, Zaver Bhujwalla, Edward Gabrielson.

  Biguanide drugs (metformin and phenformin) have drawn interest for potential cancer treatments, and laboratory studies show that some cancer cells are selectively sensitive to growth-inhibitory effects of biguanides. Examining metabolic pathways affected by biguanide treatments in cancer cells that are highly sensitive to biguanides, we found that biguanide treatment depletes cellular levels of both aspartate and NAD+. Experiments to replenish these metabolites or block steps of the aspartate-malate shuttle suggest that depletion of both metabolites, rather than either aspartate of NAD+ individually, is critical for growth-inhibitory effects of biguanide exposure. Even in sensitive cancer cells, though, biguanide treatment alone over a broad range of doses only inhibits cell replication without significantly affecting cell viability. Noting that clinical observations of biguanide efficacy have used combinations of agents that typically include cisplatin, we found that biguanide treatment at a cytostatic level substantially decreases survival of lung cancer and breast cancer cells when co-treated with cisplatin at doses that alone are also non-cytotoxic. This striking enhancement of cisplatin toxicity by biguanides depends on reductions of levels of NAD+ and aspartate, since addition of either of these metabolites prevented this potentiation of cisplatin cytotoxicity. Thus, biguanide drugs can have cytotoxic effects when used in combination with other cancer drugs, such as cisplatin, and depleting cellular levels of NAD+ and aspartate is critical for enhancing the cytotoxicity of cisplatin by biguanide drugs in sensitive cancer cells.

Keywords:  Biguanides; aspartate; cisplatin; metformin; nad; phenformin

DOI:  https://doi.org/10.1080/15384047.2021.1982599
Angew Chem Int Ed Engl. 2021 Nov 05.

Diazaborines Are a Versatile Platform to Develop ROS-Responsive Antibody Drug Conjugates*.

João P M António, Joana Inês Carvalho, Ana S André, Joana N R Dias, Sandra I Aguiar, Hélio Faustino, Ricardo M R M Lopes, Luis F Veiros, Gonçalo J L Bernardes, Frederico A da Silva, Pedro M P Gois.

  Antibody-drug conjugates (ADCs) are a new class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells. In this study we show for the first time the synthesis of a reactive-oxygen-species (ROS)-responsive ADC (VL-DAB31-SN-38) that is highly selective and cytotoxic to B-cell lymphoma (CLBL-1 cell line, IC50 value of 54.1 nM). The synthesis of this ADC was possible due to the discovery that diazaborines (DABs) are a very effective ROS-responsive unit that are also very stable in buffer and in plasma. DFT calculations performed on this system revealed a favorable energetic profile (ΔGR=-74.3 kcal mol-1 ) similar to the oxidation mechanism of aromatic boronic acids. DABs' very fast formation rate and modularity enabled the construction of different ROS-responsive linkers featuring self-immolative modules, bioorthogonal functions, and bioconjugation handles. These structures were used in the site-selective functionalization of a VL antibody domain and in the construction of the homogeneous ADC.

Keywords:  antibody-drug conjugates; boronic acids; cleavable linkers; diazaborines; reactive oxygen species

DOI:  https://doi.org/10.1002/anie.202109835
Front Oncol. 2021 ;11 740720

High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy.

Marco Fiorillo, Béla Ózsvári, Federica Sotgia, Michael P Lisanti.

  Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the "metabolically fittest" cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Therefore, we propose that the "energetically fittest" cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be naturally-selected for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model in vivo. Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells.

Keywords:  ATP; anti-oxidant capacity; bedaquiline; cancer stem cells (CSCs); dormancy; metastasis; mitochondria; multi-drug resistance

DOI:  https://doi.org/10.3389/fonc.2021.740720
Small. 2021 Nov 02. e2103868

Chemodynamic Therapy via Fenton and Fenton-Like Nanomaterials: Strategies and Recent Advances.

Chenyang Jia, Yuxin Guo, Fu-Gen Wu.

  Chemodynamic therapy (CDT), a novel cancer therapeutic strategy defined as the treatment using Fenton or Fenton-like reaction to produce •OH in the tumor region, was first proposed by Bu, Shi, and co-workers in 2016. Recently, with the rapid development of Fenton and Fenton-like nanomaterials, CDT has attracted tremendous attention because of its unique advantages: 1) It is tumor-selective with low side effects; 2) the CDT process does not depend on external field stimulation; 3) it can modulate the hypoxic and immunosuppressive tumor microenvironment; 4) the treatment cost of CDT is low. In addition to the Fe-involved CDT strategies, the Fenton-like reaction-mediated CDT strategies have also been proposed, which are based on many other metal elements including copper, manganese, cobalt, titanium, vanadium, palladium, silver, molybdenum, ruthenium, tungsten, cerium, and zinc. Moreover, CDT has been combined with other therapies like chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy for achieving enhanced anticancer effects. Besides, there have also been studies that extend the application of CDT to the antibacterial field. This review introduces the latest advancements in the nanomaterials-involved CDT from 2018 to the present and proposes the current limitations as well as future research directions in the related field.

Keywords:  Fenton/Fenton-like reactions; antibacterial; anticancer; chemodynamic therapy; reactive oxygen species

DOI:  https://doi.org/10.1002/smll.202103868
Front Cell Dev Biol. 2021 ;9 751301

Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis.

Félix A Urra, Sebastián Fuentes-Retamal, Charlotte Palominos, Yarcely A Rodríguez-Lucart, Camila López-Torres, Ramiro Araya-Maturana.

  The role of metabolism in tumor growth and chemoresistance has received considerable attention, however, the contribution of mitochondrial bioenergetics in migration, invasion, and metastasis is recently being understood. Migrating cancer cells adapt their energy needs to fluctuating changes in the microenvironment, exhibiting high metabolic plasticity. This occurs due to dynamic changes in the contributions of metabolic pathways to promote localized ATP production in lamellipodia and control signaling mediated by mitochondrial reactive oxygen species. Recent evidence has shown that metabolic shifts toward a mitochondrial metabolism based on the reductive carboxylation, glutaminolysis, and phosphocreatine-creatine kinase pathways promote resistance to anoikis, migration, and invasion in cancer cells. The PGC1a-driven metabolic adaptations with increased electron transport chain activity and superoxide levels are essential for metastasis in several cancer models. Notably, these metabolic changes can be determined by the composition and density of the extracellular matrix (ECM). ECM stiffness, integrins, and small Rho GTPases promote mitochondrial fragmentation, mitochondrial localization in focal adhesion complexes, and metabolic plasticity, supporting enhanced migration and metastasis. Here, we discuss the role of ECM in regulating mitochondrial metabolism during migration and metastasis, highlighting the therapeutic potential of compounds affecting mitochondrial function and selectively block cancer cell migration.

Keywords:  ECM stiffness; OXPHOS (oxidative phosphorylation); TCA cycle; integrin; metabolic shift; migrastatics; migrating cancer cells

DOI:  https://doi.org/10.3389/fcell.2021.751301
Turk J Pharm Sci. 2021 10 28. 18(5): 604-608

In Vitro Cytotoxicity and Oxidative Stress Evaluation of Valerian (Valeriana officinalis) Methanolic Extract in Hepg2 and Caco2 Cells

Mehtap Kara, Ecem Dilara Alparslan, Ezgi Öztaş, Özlem Nazan Erdoğan.

   Objectives: Traditional treatment methods are becoming popular and commonly used in many societies and have become the first treatment option for most people. While some of these methods are helpful, they can interact with medications the patient is taking for another disease and cause a variety of life-threatening risks. Valerian (catweed) plant is used in traditional medicine as a sleep aid due to its sedative effects. Valerian may also exert anticancer effect in vitro.
Materials and Methods: In this study, the cytotoxicty and oxidative stress effects of valerian root extract were evaluated in human liver hepatocellular carcinoma (Hepg2) and human colorectal adenocarcinoma (Caco2) cell lines. The cytotoxicity was evaluated via the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. Total reactive oxygen species analysis was performed via a 2',7'-dichlorodihydrofluorescein diacetate assay in flow cytometry.
Results: Inhibition concentration 50 values were calculated as 936.6 and 1097.5 µg/mL in the Hepg2 and Caco2 cell lines, respectively. It was observed that valerian root extract did not induce oxidative stress in HepG2 and Caco2 cell lines.
Conclusion: These results indicate that the use of valerian root extract as an alternative method in cancer treatment may not be effective and may cause a risk for public health. On the other hand, it may be safe at recommended tolerated concentrations since it does not cause oxidative stress.

Keywords:  Caco2; HepG2; MTT; Valeriana officinalis; oxidative stress

DOI:  https://doi.org/10.4274/tjps.galenos.2021.04903
Adv Healthc Mater. 2021 Nov 02. e2102038

Self-Delivery Nanomedicine for Glutamine-Starvation Enhanced Photodynamic Tumor Therapy.

Lin-Ping Zhao, Shao-Yi Chen, Rong-Rong Zheng, Ren-Jiang Kong, Xiao-Na Rao, A-Li Chen, Hong Cheng, Da-Wei Zhang, Shi-Ying Li, Xi-Yong Yu.

  Glutamine metabolism of tumor cells plays a crucial role in maintaining cell homeostasis and reducing oxidative damage. Herein, a valid strategy of inhibiting glutamine metabolism is proposed to amplify the oxidative damage of photodynamic therapy (PDT) to tumor cells. Specifically, we develop a drug co-delivery system (designated as CeV) based on chlorine e6 (Ce6) and V9302 via the self-assembly technology. In spite of the strong hydrophobicity of therapeutic agents, the assembled CeV holds a favorable dispersibility in water and an improved cellular uptake capability. Under light irradiation, the internalized CeV is capable of generating abundant ROS for PDT. More importantly, CeV could reduce the uptake of glutamine through V9302-mediated ASCT2 inhibition, leading to a reduced GSH production and an amplified oxidative stress. As a result, CeV has a robust PDT efficacy on tumor inhibition by the blockade of glutamine transport. Notably, CeV exhibits a superiority on tumor suppression over the single treatment as well as the combined administration of Ce6 and V9302, which indicates the advantage of CeV for synergistic treatment. It may serve as a novel nanoplatform for developing drug co-delivery system to improve PDT efficiency by inhibiting cell metabolism. This article is protected by copyright. All rights reserved.

Keywords:  co-delivery; glutamine metabolism; oxidative stress; photodynamic therapy; self-assembly

DOI:  https://doi.org/10.1002/adhm.202102038