bims-rehoca 2021-09-19 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–09–19
28 papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

Picropodophyllotoxin induces G1/S cell cycle arrest and apoptosis in human colorectal cancer cells via ROS generation and activation of p38 MAPK signaling pathway.
Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells.
Ir(III) Complex Dimer Nanoparticles for Photodynamic Therapy.
Metal-Organic Framework-Based Nanoagents for Effective Tumor Therapy by Dual Dynamics-Amplified Oxidative Stress.
Pro-Oxidant Effect of Resveratrol on Human Breast Cancer MCF-7 Cells is Associated with CK2 Inhibition.
A photo and tumor microenvironment activated nano-enzyme with enhanced ROS generation and hypoxia relief for efficient cancer therapy.
Tuning the Toxicity of Reactive Oxygen Species into Advanced Tumor Therapy.
Reactive oxygen species-responsive polydopamine nanoparticles for targeted and synergistic chemo and photodynamic anticancer therapy.
The petroleum ether extract of Brassica rapa L. induces apoptosis of lung adenocarcinoma cells via the mitochondria-dependent pathway.
TAD1822-7 induces ROS-mediated apoptosis of HER2 positive breast cancer by decreasing E-cadherin in an EphB4 dependent manner.
Ozone induces BEL7402 cell apoptosis by increasing reactive oxygen species production and activating JNK.
Selenite induced breast cancer MCF7 cells apoptosis through endoplasmic reticulum stress and oxidative stress pathway.
The Anti-Proliferative Lichen-Compound Protolichesterinic Acid Inhibits Oxidative Phosphorylation and Is Processed via the Mercapturic Pathway in Cancer Cells.
CeO2 QDs anchored on MnO2 nanoflowers with multiple synergistic effects for amplified tumour therapy.
Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy.
W-Doped TiO2 Nanorods for Multimode Tumor Eradication in Osteosarcoma Models under Single Ultrasound Irradiation.
A tumor microenvironment responsive nanosystem for chemodynamic/chemical synergistic theranostics of colorectal cancer.
δ-Tocotrienol sensitizes and re-sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis.
Mitochondria: endosymbiont bacteria DNA sequence as a target against cancer.
Combining Sodium Butyrate With Cisplatin Increases the Apoptosis of Gastric Cancer In Vivo and In Vitro via the Mitochondrial Apoptosis Pathway.
2,5-dimethyl celecoxib induces apoptosis and autophagy via activation of ROS/JNK axis in nasopharyngeal carcinoma cells.
Areca nut extract (ANE) inhibits the progression of hepatocellular carcinoma cells via activation of ROS production and activation of autophagy.
Elemene Nanoemulsion Inhibits Metastasis of Breast Cancer by ROS Scavenging.
Selective synergistic anticancer effects of cisplatin and oridonin against human p53-mutant esophageal squamous carcinoma cells.
Cashing in on ferroptosis against tumor cells: Usher in the next chapter.
PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells.
Transferrin-Conjugated Erianin-Loaded Liposomes Suppress the Growth of Liver Cancer by Modulating Oxidative Stress.
Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer.

J Microbiol Biotechnol. 2021 Sep 15. 31(1):

Picropodophyllotoxin induces G1/S cell cycle arrest and apoptosis in human colorectal cancer cells via ROS generation and activation of p38 MAPK signaling pathway.

Seung-On Lee, Ah-Won Kwak, Mee-Hyun Lee, Ji-Hye Seo, Seung-Sik Cho, Goo Yoon, Jung-Il Chae, Sang Hoon Joo, Jung-Hyun Shim.

  Picropodophyllotoxin (PPT), an epimer of podophyllotoxin, is derived from the roots of Podophyllum hexandrum and it exerts various biological effects, such as anti- proliferation activity. However, the effect of PPT on colorectal cancer cells and the cellular mechanisms have not been studied. In the present study, we explored the anticancer activity and its underlying mechanisms of PPT in HCT116 cells. The MTT assay was used to monitor the cell viability. The flow cytometry was used to evaluate cell cycle distribution, induction of apoptosis, level of reactive oxygen species (ROS), assessment of the mitochondrial membrane potential (Δψm) and multi-caspase activity. western blotting assay was performed to detect the expression of cell cycle regulatory proteins, apoptosis-related proteins, and p38MAPK. We found that PPT induced apoptosis, cell cycle arrest at the G1-phase, and reactive oxygen species production in HCT116 cell line. In addition, PPT enhanced phosphorylation of p38 MAPK that regulates apoptosis and PPT induced apoptosis. The phosphorylation of p38 MAPK was inhibited by antioxidant agent (N-acetyl-L-cysteine, NAC) and the p38 inhibitor (SB203580). PPT induced depolarization of the mitochondrial inner membrane and caspase dependent apoptosis, which was attenuated by exposure to Z VAD FMK. Overall, these data indicate that PPT induces G1/S arrest and apoptosis via the ROS generation and activation of p38 MAPK signaling pathway.

Keywords:  Picropodophyllotoxin; apoptosis; cell cycle arrest; colon cancer; p38; reactive oxygen species

DOI:  https://doi.org/10.4014/jmb.2109.09012
Int J Biol Sci. 2021 ;17(13): 3456-3475

Thymoquinone Suppresses the Proliferation, Migration and Invasiveness through Regulating ROS, Autophagic Flux and miR-877-5p in Human Bladder Carcinoma Cells.

Xuejian Zhou, Feifan Wang, Hongshen Wu, Xianwu Chen, Yan Zhang, Juntao Lin, Yueshu Cai, Jiayong Xiang, Ning He, Zhenghui Hu, Xiaodong Jin.

  Bladder carcinoma is among the top 10 most frequently diagnosed cancer types in the world. As a phytochemical active metabolic, thymoquinone (TQ) is extracted from seeds of Nigella sativa, possessing various biological properties in a wide range of diseases. Moreover, the outstanding anti-cancer effect of TQ is attracting increasing attentions. In certain circumstances, moderate autophagy is regarded to facilitate the adaptation of malignant cells to different stressors. Conversely, closely linked with the mitochondrial membrane potential (MMP) loss, the upregulation of intracellular reactive oxygen species (ROS) is reported to activate the cell apoptosis in many cancer types. Furthermore, the vital effects of microRNAs in the pathological processes of cancer cells have also been confirmed by previous studies. The present research confirms that TQ restrains the viability, proliferation, migration and invasion through activating caspase-dependent apoptosis in bladder carcinoma cells, which is mediated by TQ induced ROS increase in bladder carcinoma cells. Furthermore, TQ is proved to block the fusion of autophagosomes and lysosomes, causing the accumulation of autophagosomes and subsequent cell apoptosis. In addition, TQ is also found to initiate the miR-877-5p/PD-L1 axis, which suppresses the epithelial mesenchymal transition (EMT) and invasion of bladder carcinoma cells. Taken together, TQ induces the apoptosis through upregulating ROS level and impairing autophagic flux, and inhibiting the EMT and cell invasion via activating the miR-877-5p/PD-L1 axis in bladder carcinoma cells.

Keywords:  Autophagic flux; Bladder carcinoma; Epithelial mesenchymal transition; Reactive oxygen specifics; Thymoquinone; miR-877-5p/PD-L1 axis

DOI:  https://doi.org/10.7150/ijbs.60401
ACS Med Chem Lett. 2021 Sep 09. 12(9): 1374-1379

Ir(III) Complex Dimer Nanoparticles for Photodynamic Therapy.

Yingjie Liu, Dongxia Zhu, Zhigang Xie.

Iridium compounds are versatile in catalysis and photodynamic therapy. We present two Ir(III) complex dimers that can self-assemble into nanoparticles in the absence of adjuvant or surfactants. The formed nanoparticles possess a spherical morphology and robust colloidal stability and could be internalized by cancer cells. The Ir(III) complex nanoparticles have relatively strong photodynamic activity upon irradiation, which includes type I and type II reactive oxygen species. The generated reactive oxygen species could effectively induce cell death upon irradiation. This work highlights the potential of metal complexes and their nanoparticles in cancer treatment.

DOI: https://doi.org/10.1021/acsmedchemlett.1c00362
ACS Appl Mater Interfaces. 2021 Sep 16.

Metal-Organic Framework-Based Nanoagents for Effective Tumor Therapy by Dual Dynamics-Amplified Oxidative Stress.

Jiajie Chen, Yitong Wang, Huicong Niu, Yuwei Wang, Aijun Wu, Chaoqin Shu, Yufang Zhu, Yuhai Bian, Kaili Lin.

  Overproduction of reactive oxygen species (ROS) within tumors can cause oxidative stress on tumor cells to induce death, which has motivated us to develop ROS-mediated tumor therapies, such as typical photodynamic therapy (PDT) and Fenton reaction-mediated chemodynamic therapy (CDT). However, these therapeutic modalities suffer from compromised treatment efficacy owing to their limited generation of highly reactive ROS in a tumor microenvironment (TME). In this work, a nanoscale iron-based metal-organic framework, MIL-101(Fe), is synthesized as a Fenton nanocatalyst to perform the catalytic conversion of hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) under the acidic environment and as a biocompatible and biodegradable nanocarrier to deliver a 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) photosensitizer for light-activated singlet oxygen (1O2) generation. By coupling such chemodynamic/photodynamic effects, the photosensitizer-integrated nanoagents (MIL-101(Fe)@TCPP) could enable more ROS production within tumors to induce amplified oxidative damage for tumor-specific synergistic therapy. In vitro results show that MIL-101(Fe)@TCPP nanoagents achieve the acid-responsive CDT and effective PDT, and synergistic CDT/PDT provides an enhanced therapeutic effect. Ultimately, based on such synergistic therapy, MIL-101(Fe)@TCPP nanoagents cause a significant tumor growth inhibition in vivo without severe side effects, showing great potential for anti-tumor application.

Keywords:  chemodynamic therapy; metal−organic framework; photodynamic therapy; porphyrin; tumor

DOI:  https://doi.org/10.1021/acsami.1c11032
Nutr Cancer. 2021 Sep 14. 1-10

Pro-Oxidant Effect of Resveratrol on Human Breast Cancer MCF-7 Cells is Associated with CK2 Inhibition.

Paula Seixas da Costa, Patrícia Severo Ramos, Christian Ferreira, Jerson Lima Silva, Tatiana El-Bacha, Eliane Fialho.

Casein kinase 2 (CK2) plays a critical role in the proliferation and apoptosis of cancer cells. Resveratrol is a bioactive compound with anticancer and anti-inflammatory effects. This study investigated the pro-oxidant cytotoxic effects of resveratrol in association with the inhibition of CK2 activity on human breast carcinoma cells MCF-7. We showed that resveratrol and TBB, an inhibitor of CK2, decreased cell viability in a concentration dependent manner with an IC50 value of 238 µM and 106 µM after 24 h, of treatment, respectively. Resveratrol and TBB decreased CK2 activity by 1.6 and 1.4-fold, respectively, and both significantly decreased mitochondrial membrane potential. However, only resveratrol increased reactive oxygen species (ROS) levels by 1.7-fold as opposed to TBB, which did not affect ROS levels. Indeed, incubating MCF-7 cells with the antioxidant polyethylene glycol-catalase (PEG-CAT) preserved cell viability from the cytotoxic effects of resveratrol, but not from TBB toxicity. This effect seemed to be related to PEG-CAT ability to prevent CK2 inhibition induced by resveratrol incubation. In conclusion, this study demonstrated that the cytotoxic effect of resveratrol on MCF-7 cells might be associated with its pro-oxidant action, which inhibited CK2 activity, affecting cell viability and mitochondrial function.

DOI: https://doi.org/10.1080/01635581.2021.1977834
J Mater Chem B. 2021 Sep 13.

A photo and tumor microenvironment activated nano-enzyme with enhanced ROS generation and hypoxia relief for efficient cancer therapy.

Yali Chen, Yujun Cai, Xingsu Yu, Hong Xiao, Haozhe He, Zecong Xiao, Yong Wang, Xintao Shuai.

Reactive oxygen species (ROS) mediated tumor therapy strategies have exhibited great prospects and attracted increasing attention, among which photodynamic therapy (PDT) has been well-established. However, the anticancer effects of PDT are greatly limited by the hypoxic tumor microenvironment (TME). Hence, exploring a therapeutic strategy that can relieve tumor hypoxia is regarded as the key to overcoming this problem. Herein, we develop a novel nano-enzyme (MnO2@TPP-PEG) that can accurately conduct tumor-specific catalysis of H2O2 to produce oxygen through a Fenton-like reaction, leading to an enhanced PDT under the irradiation of light. More importantly, the process of catalyzing H2O2 decomposition at the tumor location can also generate a cytotoxic hydroxyl radical (˙OH), achieving an excellent chemodynamic therapy (CDT) to enhance the ROS mediated anti-cancer effect. Notably, the nano-enzyme exerts a high loading content of the photosensitizer, which minimizes the side effects probably caused by the vector.

DOI: https://doi.org/10.1039/d1tb01437d
Nanoscale Res Lett. 2021 Sep 13. 16(1): 142

Tuning the Toxicity of Reactive Oxygen Species into Advanced Tumor Therapy.

An Xie, He Li, Yumei Hao, Yujia Zhang.

  The biological functions and toxic effects of reactive oxygen species (ROS) are generally entangled. A large amount of ROS may cause oxidative damage to cell biomolecules, leading to cell death. Tumor treatment can be carried out by using the toxicity of ROS, and various nanosystems related to ROS have been designed. In fact, the level of active oxygen in the biological microenvironment can be regulated in advanced therapeutics via designed nanoscale engineering, which can open up a new direction of treatment with specific simplicity. In this progress report, the authors first introduced how ROS causes cell death. Then, recent studies on converting the inherent toxicity from ROS into advanced treatment tools are highlighted.

Keywords:  Chemodynamic therapy; Photodynamic therapy; Reactive oxygen species; Tumor therapy

DOI:  https://doi.org/10.1186/s11671-021-03599-8
Nanoscale. 2021 Sep 15.

Reactive oxygen species-responsive polydopamine nanoparticles for targeted and synergistic chemo and photodynamic anticancer therapy.

Gaole Dai, Jacky C H Chu, Cecilia Ka Wing Chan, Chung Hang Jonathan Choi, Dennis K P Ng.

A thioketal-linked dimer of 3,4-dihydroxy-L-phenylalanine was prepared which underwent self-polymerisation in the presence of doxorubicin (Dox) in an ethanol/water (1 : 4, v/v) mixture with ammonia. The resulting Dox-encapsulated polydopamine (PDA) nanoparticles were further conjugated with molecules of a zinc(II) phthalocyanine (Pc)-based photosensitiser and a peptide containing the heptapeptide QRHKPRE sequence (labelled as QRH) that can target the epidermal growth factor receptor (EGFR) overexpressed in cancer cells. Upon internalisation into these cells through receptor-mediated endocytosis, these nanoparticles labelled as PDA-Dox-Pc-QRH were disassembled gradually via cleavage of the thioketal linkages by the intrinsic intracellular reactive oxygen species (ROS). The stacked Pc molecules were then disaggregated, resulting in activation of their photosensitising property upon irradiation. The ROS generated by the activated Pc promoted further degradation of the nanoparticles and release of Dox, thereby enhancing cell death by synergistic chemo and photodynamic therapy. Systemic injection of PDA-Dox-Pc-QRH into EGFR-overexpressed tumour-bearing nude mice led to targeted delivery to the tumour, and subsequent light irradiation caused complete tumour ablation without inducing notable toxicity.

DOI: https://doi.org/10.1039/d1nr04278e
Food Funct. 2021 Sep 13.

The petroleum ether extract of Brassica rapa L. induces apoptosis of lung adenocarcinoma cells via the mitochondria-dependent pathway.

Xierenguli Halike, Jinyu Li, Pengfei Yuan, Kaimeiliya Yasheng, Min Chen, Lijie Xia, Jinyao Li.

Brassica rapa L. is one of the most popular traditional foods with a variety of biological activities. In this study, the petroleum ether extract of B. rapa was separated by silica gel column chromatography, and named BRPS, which was identified by LC-MS. The effects and pharmacological mechanisms of BRPS on the treatment of lung cancer were investigated both in vitro and in vivo. The results showed that BRPS significantly inhibited the proliferation of both human lung cancer A549 and mouse lung cancer LLC cells, while its toxicity to normal cells was lower than that of cancer cells. BRPS induced cell cycle arrest at the G2/M phase and significantly reduced the levels of CDK1 and CyclinB1 in A549 cells. Moreover, BRPS induced apoptosis in a dose-dependent manner, and increased the Bax/Bcl-2 ratio, while it decreased mitochondrial membrane potential, promoted the release of cytochrome c, activated caspase 9 and 3, and enhanced the degradation of PARP in A549 cells. Furthermore, the levels of reactive oxygen species (ROS) were also upregulated by BRPS and ROS inhibitor reversed BRPS-induced apoptosis. Importantly, BRPS significantly suppressed the growth of LLC cells in vivo without any obvious side effect on body weight and organs of mice, and increased the proportion of B cells, CD4+ T cells, CD8+ T cells and CD44+CD8+ T cells in the spleen. These results revealed that BRPS inhibited the growth of lung cancer cells through inducing cell cycle arrest, mitochondria-dependent apoptosis, and activating immunity of mice, and BRPS might be a potential anti-tumor functional food and promising agent for the treatment of lung cancer.

DOI: https://doi.org/10.1039/d1fo01547h
Life Sci. 2021 Sep 11. pii: S0024-3205(21)00941-3. [Epub ahead of print] 119954

TAD1822-7 induces ROS-mediated apoptosis of HER2 positive breast cancer by decreasing E-cadherin in an EphB4 dependent manner.

Man Zhu, Xiaoyu Tang, Zhengyan Gong, Wenjuan Tang, Yanmin Zhang.

  HER2-positive breast cancer (HER2-BC) shows the over-expression of tyrosine kinase receptor EphB4 associated with poor disease prognosis. E-cadherin is found as a survival factor in multiple models of breast cancer by suppressing reactive oxygen-mediated apoptosis. This study confirmed that both HER2 and EphB4 are positively correlated with E-cadherin in HER2-BC. Inhibition of HER2 or EphB4 is discovered to induce ROS-dependent apoptosis by decreasing E-cadherin expression in SKBR3 and MDA-MB-453 cells. TAD1822-7 (TAD), a novel biphenyl urea taspine derivative, exhibits good growth inhibition, apoptosis induction and ROS accumulation effects on SKBR3 and MDA-MB-453 cells. Mechanistic investigation revealed that TAD blockades both EphB4 positive signal transduction and activation of HER2 signal transduction, thereby suppressing E-cadherin/TGF-β/p-Smad2/3 signaling axis to elicit ROS-dependent endogenous mitochondrial apoptosis. Together, these findings not only provide a new approach for HER2-BC therapy but also increase our understanding of the regulating effect of E-cadherin by HER2 and EphB4 in ROS-mediated apoptosis.

Keywords:  Apoptosis; Breast cancer; E-cadherin; EphB4; HER2; TAD1822-7

DOI:  https://doi.org/10.1016/j.lfs.2021.119954
Ann Transl Med. 2021 Aug;9(15): 1257

Ozone induces BEL7402 cell apoptosis by increasing reactive oxygen species production and activating JNK.

Shuiying Tang, Bihong Xu, Jincheng Li, Meifeng Zhong, Ziyang Hong, Wei Zhao, Tao Zeng, Xiaofeng He.

   Background: Oxidative stress is an important factor in the modulation of both tumorigenesis and anticancer responses. Ozone (O3) is a strong oxidant that causes redox reactions and exerts anticancer effects in various types of cancer cells. However, the pathways involved in O3-induced cell death are not well understood.
Methods: In vitro human hepatocellular carcinoma (HCC) BEL7402 cells were treated with various O3 concentrations to evaluate O3 cytotoxicity by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The regulatory mechanisms were analyzed by western blot analysis. In vivo, an HCC model was established to evaluate the inhibition of HCC with O3 treatment.
Results: In vitro cells treated with O3 exhibited a round and small morphology with nuclear shrinkage and fragmentation. The CCK-8 assay confirmed the potent cytotoxic activity of O3 against BEL7402 cells (IC50 value of 5 µg/mL). Acridine orange/ethidium bromide (AO/EB) staining revealed apoptosis of BEL7402 cells after O3 treatment. Flow cytometry analysis showed that S phase cell cycle arrest and apoptosis increased with O3 exposure. In addition, O3 exposure reduced the mitochondrial membrane potential (ΔΨm) and induced reactive oxygen species (ROS) accumulation. Western blot analysis showed that O3 exposure reduced B-cell lymphoma 2 (BCL-2) expression and increased cleaved poly ADP-ribose polymerase (PARP), cytochrome C (Cyt-C), caspase-3, caspase-9, and p-JNK expression. In vivo, treatment with intratumor injection O3 (20 µg/mL) inhibited HCC growth.
Conclusions: Overall, our findings showed that O3 induces BEL7402 cell apoptosis via the intrinsic mitochondria-dependent pathway. Therefore, O3 has therapeutic potential for HCC.

Keywords:  Ozone (O3); apoptosis; hepatocellular carcinoma (HCC); reactive oxygen species (ROS)

DOI:  https://doi.org/10.21037/atm-21-3233
Chem Biol Interact. 2021 Sep 11. pii: S0009-2797(21)00289-1. [Epub ahead of print] 109651

Selenite induced breast cancer MCF7 cells apoptosis through endoplasmic reticulum stress and oxidative stress pathway.

Lina Cao, Jingjing Zhang, Yan Du, Min Sun, Yue Xiang, Yulu Sheng, Xiangmei Ren, Jihong Shao.

  Selenium is an essential trace element for human, and has anti-tumor effects. In this study, we investigated the anti-tumor activity of sodium selenite (Na2SeO3) and explored its possible mechanisms involved in a breast cancer cell line. We found that Na2SeO3 could inhibit the cell viability of MCF7 cells, yet with minimal damage to human umbilical vein endothelial cells (HUVECs). The results of Hoechst staining and Western Blot showed that Na2SeO3 induced apoptosis of MCF7 cells. Na2SeO3 activated endoplasmic reticulum stress (ERS), as evidenced by the up-regulation of ERS-related proteins, including ATF6, p-eIF2α, ATF4, and CHOP, and the down-regulation of PERK. ATF6, p-eIF2α and apoptosis were decreased by pre-treatment with an ERS inhibitor (4-PBA). Na2SeO3 activated oxidative stress (OS) through increasing ROS generation and decreasing mitochondrial membrane potential (MMP) which induced apoptosis. Pre-treatment with an antioxidant (NAC) attenuated Na2SeO3-induced OS and cell apoptosis. Furthermore, ERS and OS had mutual effects. Pre-treatment with 4-PBA could act against the up-regulation of ROS and the down-regulation of MMP. Pre-treatment with NAC attenuated the expression of ATF6. At the same time, we found that treatment with Na2SeO3 promoted the phosphorylation of p38 and JNK, while inhibiting the phosphorylation of ERK. However, the up-regulation was inhibited after pre-treatment of NAC, and pre-treatment with 4-PBA inhibited the increase only of p38. Based on these results, our study provides a mechanistic understanding of how Na2SeO3 has antitumor effects against MCF7 cells through the OS and ERS pathway. OS and ERS interact with each other, and p38 is regulated by them.

Keywords:  Apoptosis; Breast cancer; Endoplasmic reticulum stress; Oxidative stress; Sodium selenite; p38

DOI:  https://doi.org/10.1016/j.cbi.2021.109651
Planta Med. 2021 Sep 14.

The Anti-Proliferative Lichen-Compound Protolichesterinic Acid Inhibits Oxidative Phosphorylation and Is Processed via the Mercapturic Pathway in Cancer Cells.

Freyr Jóhannsson, Paulina Cherek, Maonian Xu, Óttar Rolfsson, Helga M Ögmundsdóttir.

The lichen compound protolichesterinic acid (PA) has an anti-proliferative effect against several cancer cell lines of different origin. This effect cannot be explained by the known inhibitory activity of PA against 5- and 12-lipoxygenases. The aim was therefore to search for mechanisms for the anti-proliferative activity of PA. Two cancer cell lines of different origin, both sensitive to anti-proliferative effects of PA, were selected for this study, T-47D from breast cancer and AsPC-1 from pancreatic cancer. Morphological changes were assessed by transmission electron microscopy, HPLC coupled with TOF spectrometry was used for metabolomics, mitochondrial function was measured using the Agilent Seahorse XFp Real-time ATP assay and glucose/lactate levels by radiometry. Levels of glutathione, NADP/NADPH and reactive oxygen species [ROS] were measured by luminescence. Following exposure to PA both cell lines showed structural changes in mitochondria that were in line with a measured reduction in oxidative phosphorylation and increased glycolysis. These changes were more marked in T-47D, which had poorer mitochondrial function at baseline. PA was processed and expelled from the cells via the mercapturic pathway, which consumes glutathione. Nevertheless, glutathione levels were increased after 24 hours of exposure to PA, implying enhanced synthesis. Redox balance was not much affected and ROS levels were not increased. We conclude that PA is metabolically processed and expelled from cells, leading indirectly to increased glutathione levels with minimal effects on redox balance. The most marked effect was on mitochondrial structure and metabolic function implying that effects of PA may depend on mitochondrial fitness.

DOI: https://doi.org/10.1055/a-1579-6454
Colloids Surf B Biointerfaces. 2021 Sep 08. pii: S0927-7765(21)00547-6. [Epub ahead of print]208 112103

CeO2 QDs anchored on MnO2 nanoflowers with multiple synergistic effects for amplified tumour therapy.

Yuyan Yan, Yafei Hou, Huijun Zhang, Wenqing Gao, Renlu Han, Jiancheng Yu, Long Xu, Keqi Tang.

  Chemodynamic therapy (CDT) is an emerging tumour-specific therapeutic technology. However, the relatively insufficient catalytic activity of CDT agents in the tumour microenvironment (TME) limits their biomedical application. In addition, severe hypoxia and glutathione (GSH) overexpression in the TME greatly limit the antitumour efficiency of monotherapy. Herein, a cancer cell membrane-camouflaged and ultrasmall CeO2-decorated MnO2 (mMC) composite is developed for amplified CDT, photodynamic therapy (PDT) and photothermal therapy (PTT). Due to the homotypic targeting ability of cancer cell membranes, mMC nanoparticles preferentially accumulate in tumour tissue. In the TME, CeO2 acts as a highly efficient CDT agent to convert endogenous H2O2 to toxic reactive oxygen species (ROS) for killing cancer cells. Meanwhile, MnO2 irradiated with near-infrared (NIR) light displays prominent hyperthermia and ROS generation performance to perform PTT and PDT. Moreover, MnO2 can produce oxygen to ameliorate hypoxia and deplete GSH to relieve the antioxidant capability of tumours, which is beneficial to the simultaneous augmentation of PDT and CDT. Most importantly, the catalytic activity of CeO2 was greatly improved by hyperthermia. Consequently, a significantly enhanced therapeutic efficiency was obtained by the above multiple synergistic effects. This work provides a proof of concept for amplified tumour therapy by synchronously self-supplying oxygen, consuming GSH, and enhancing catalytic activity.

Keywords:  Amplified tumour therapy; CeO(2); Chemodynamic therapy; Phototherapy; Synergistic effect

DOI:  https://doi.org/10.1016/j.colsurfb.2021.112103
Adv Mater. 2021 Sep 18. e2104641

Sono-Controllable and ROS-Sensitive CRISPR-Cas9 Genome Editing for Augmented/Synergistic Ultrasound Tumor Nanotherapy.

Yinying Pu, Haohao Yin, Caihong Dong, Huijing Xiang, Wencheng Wu, Bangguo Zhou, Dou Du, Yu Chen, Huixiong Xu.

  The potential of the cluster regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9)-based therapeutic genome editing is severely hampered by the difficulties in precise regulation of the in vivo activity of the CRISPR-Cas9 system. Herein, sono-controllable and reactive oxygen species (ROS)-sensitive sonosensitizer-integrated metal-organic frameworks (MOFs), denoted as P/M@CasMTH1, are developed for augmented sonodynamic therapy (SDT) efficacy using the genome-editing technology. P/M@CasMTH1 nanoparticles comprise singlet oxygen (1 O2 )-generating MOF structures anchored with CRISPR-Cas9 systems via 1 O2 -cleavable linkers, which serve not only as a delivery vector of CRISPR-Cas9 targeting MTH1, but also as a sonoregulator to spatiotemporally activate the genome editing. P/M@CasMTH1 escapes from the lysosomes, harvests the ultrasound (US) energy and converts it into abundant 1 O2 to induce SDT. The generated ROS subsequently trigger cleavage of ROS-responsive thioether bonds, thus inducing controllable release of the CRISPR-Cas9 system and initiation of genome editing. The genomic disruption of MTH1 conspicuously augments the therapeutic efficacy of SDT by destroying the self-defense system in tumor cells, thereby causing cellular apoptosis and tumor suppression. This therapeutic strategy for synergistic MTH1 disruption and abundant 1 O2 generation provides a paradigm for augmenting SDT efficacy based on the emerging nanomedicine-enabled genome-editing technology.

Keywords:  ROS responsive; genomic editing; metal-organic frameworks; sonodynamic therapy; tumor therapy

DOI:  https://doi.org/10.1002/adma.202104641
ACS Appl Mater Interfaces. 2021 Sep 17.

W-Doped TiO2 Nanorods for Multimode Tumor Eradication in Osteosarcoma Models under Single Ultrasound Irradiation.

Bijiang Geng, Xue Yang, Ping Li, Wenyan Shi, Dengyu Pan, Longxiang Shen.

  Sonosensitizers play crucial roles in the controlled production of reactive oxygen species (ROS) under ultrasound (US) irradiation with high tissue-penetration depth for noninvasive solid tumor therapy. It is desirable to fabricate structurally simple yet multifunctional sonosensitizers from ultrafine nanoparticles for ROS-based multimode therapy to overcome monomode limitations such as low ROS production yields and endogenous reductive glutathione (GSH) to ROS-based treatment resistance. We report the facile high-temperature solution synthesis of ultrafine W-doped TiO2 (W-TiO2) nanorods for exploration of their sonodynamic, chemodynamic, and GSH-depleting activities in sonodynamic-chemodynamic combination tumor therapy. We found that W5+ and W6+ ions doped in W-TiO2 nanorods play multiple roles in enhancing their ROS production. First, W doping narrows the band gap from 3.2 to 2.3 eV and introduces oxygen and Ti vacancies for enhancing their sonodynamic performance. Second, W5+ doping endows W-TiO2 nanorods with Fenton-like reaction activity to produce •OH from endogenous H2O2 in the tumor. Third, W6+ ions reduce endogenous GSH to glutathione disulfide (GSSG) and, in turn, form W5+ ions that further enhance their chemodynamic activity, which greatly modifies thae oxidation-reduction tumor microenvironment in the tumor. In vivo experiments display the excellent ability of W-TiO2 nanorods for enhanced tumor eradication in human osteosarcoma models under single US irradiation. Importantly, the ultrafine nanorod morphology facilitates rapid excretion from the body, displaying no significant systemic toxicity. Our work suggests that multivalent metal doping in ultrafine nanomaterials is an effective and simple strategy for the introduction of new functions for ROS-based multimode therapy.

Keywords:  GSH depletion; chemodynamic therapy; sonodynamic therapy; tumor microenvironment; ultrafine W-TiO2 nanorods

DOI:  https://doi.org/10.1021/acsami.1c14701
Theranostics. 2021 ;11(18): 8909-8925

A tumor microenvironment responsive nanosystem for chemodynamic/chemical synergistic theranostics of colorectal cancer.

Liying Wang, Jingya Xia, Hongjie Fan, Min Hou, Huiyang Wang, Xiaoyan Wang, Ke Zhang, Liping Cao, Xiangrui Liu, Jun Ling, Hong Yu, Xia Wu, Jihong Sun.

  Rationale: The synergism of new modalities alongside chemodynamic therapy into common chemotherapy has shown promising potential in clinical applications. This paper reports a tumor microenvironment-responsive nanosystem for chemodynamic/chemical synergistic therapy and magnetic resonance imaging (MRI). Methods: The biodegradable nanosystem is synthesized using a surface-modified chain transfer agent for surface-initiated living radical polymerization of the chemotherapeutic drug. Results: In this nanosystem, named CAMNSN@PSN38, the cycling time and solubility of the chemotherapeutic drug are improved. The nanoparticles delivered to tumor tissues gradually release the chemotherapeutic drug and Mn2+ through glutathione (GSH)-triggered biodegradation in the tumor microenvironment. SN38, the released chemotherapeutic drug, not only shows excellent chemical therapy effects but also improves the generation of H2O2. Furthermore, with the Fenton-like agent Mn2+, the generation of reactive oxygen species (ROS) is improved markedly. Finally, CAMNSN@PSN38 shows excellent inhibition of tumor growth in three colorectal cancer tumor models, with an improved accumulation of ROS and controlled release of SN38. Conclusions: The CAMNSN@PSN38-mediated chemodynamic/chemical synergistic therapy provides a promising paradigm for the treatment and MRI-guided therapy of colorectal cancer.

Keywords:  Chemodynamic therapy; Magnetic resonance imaging; Microenvironment-responsive; Nanotheranostics; Synergistic therapy

DOI:  https://doi.org/10.7150/thno.61651
Cell Prolif. 2021 Sep 14. e13111

δ-Tocotrienol sensitizes and re-sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis.

Fabrizio Fontana, Monica Marzagalli, Michela Raimondi, Valentina Zuco, Nadia Zaffaroni, Patrizia Limonta.

   OBJECTIVES: Among gynaecologic malignancies, ovarian cancer (OC) represents the leading cause of death for women worldwide. Current OC treatment involves cytoreductive surgery followed by platinum-based chemotherapy, which is associated with severe side effects and development of drug resistance. Therefore, new therapeutic strategies are urgently needed. Herein, we evaluated the anti-tumour effects of Vitamin E-derived δ-tocotrienol (δ-TT) in two human OC cell lines, IGROV-1 and SKOV-3 cells.
MATERIALS AND METHODS: MTT and Trypan blue exclusion assays were used to assess δ-TT cytotoxicity, alone or in combination with other molecules. δ-TT effects on cell cycle, apoptosis, ROS generation and MAPK phosphorylation were investigated by flow cytometry, Western blot and immunofluorescence analyses. The synergism between δ-TT and chemotherapy was evaluated by isobologram analysis.
RESULTS: We demonstrated that δ-TT could induce cell cycle block at G1-S phase and mitochondrial apoptosis in OC cell lines. In particular, we found that the proapoptotic activity of δ-TT correlated with mitochondrial ROS production and subsequent JNK and p38 activation. Finally, we observed that the compound was able to synergize with cisplatin, not only enhancing its cytotoxicity in IGROV-1 and SKOV-3 cells but also re-sensitizing IGROV-1/Pt1 cell line to its anti-tumour effects.
CONCLUSIONS: δ-TT triggers G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis in OC cells and sensitizes them to platinum treatment, thus representing an interesting option for novel chemopreventive/therapeutic strategies for OC.

Keywords:  MAPK; ROS; apoptosis; cisplatin; ovarian cancer; tocotrienols

DOI:  https://doi.org/10.1111/cpr.13111
Cancer Sci. 2021 Sep 17.

Mitochondria: endosymbiont bacteria DNA sequence as a target against cancer.

Hiroki Nagase, Takayoshi Watanabe, Nobuko Koshikawa, Seigi Yamamoto, Keizo Takenaga, Jason Lin.

  As the energy factory for the cell, the mitochondrion, through its role of adenosine triphosphate production by oxidative phosphorylation, can be regarded as the guardian of well-regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria is often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression and metastasis of tumor cells. Such pathogenic mtDNA aberrations are likely to increase and occasionally be homoplasmic in cancer cells and, intriguingly, in normal cells in the proximity of tumor microenvironments (TME) as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. Here we discuss a promising novel therapeutic strategy, utilizing the sequence-specific properties of pyrrole-imidazole polyamide-triphenylphosphonium conjugates, against cancer for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance.

Keywords:  Age-related disorder; Anti-cancer therapy; Apoptosis; Autophagy; BCL family; Exocytosis; Mitochondria; Mitochondrial disease; Mitochondrial quality control (MQC); Mitophagy; Mutation; Polymorphism; Pyrrole-imidazole polyamide; Reactive oxygen species (ROS); Senescence; Triphenylphosphonium (TPP); mtDNA

DOI:  https://doi.org/10.1111/cas.15143
Front Pharmacol. 2021 ;12 708093

Combining Sodium Butyrate With Cisplatin Increases the Apoptosis of Gastric Cancer In Vivo and In Vitro via the Mitochondrial Apoptosis Pathway.

Yangbo Li, Pengzhan He, Yinghui Liu, Mingming Qi, Weiguo Dong.

  Introduction: The gastrointestinal malignancy, gastric cancer (GC), has a high incidence worldwide. Cisplatin is a traditional chemotherapeutic drug that is generally applied to treat cancer; however, drug tolerance affects its efficacy. Sodium butyrate is an intestinal flora derivative that has general anti-cancer effects in vitro and in vivo via pro-apoptosis effects and can improve prognosis in combination with traditional chemotherapy drugs. The present study aimed to assess the effect of sodium butyrate combined with cisplatin on GC. Methods: A Cell Counting Kit-8 assay was used to assess the viability of GC cells in vitro. Hoechst 33,258 staining and Annexin V-Phycoerythrin/7-Aminoactinomycin D were used to qualitatively and quantitatively detect apoptosis in GC cells. Intracellular reactive oxygen species (ROS) measurement and a mitochondrial membrane potential (MMP) assay kit were used to qualitatively and quantitatively reflect the function of mitochondria in GC cells. Western blotting was used to verify the above experimental results. A nude mouse xenograft tumor model was used to evaluate the anti-tumor efficacity of sodium and cisplatin butyrate in vivo. Results: Cisplatin combined with sodium butyrate increased the apoptosis of GC cells. In the nude mouse xenograft tumor model, sodium butyrate in combination with cisplatin markedly inhibited the growth of the tumor more effectively than either single agent. The combination of sodium butyrate and cisplatin increased the intracellular ROS, decreased the MMP, and suppressed the invasion and migration abilities of GC cells. Western blotting verified that the combination of sodium butyrate and cisplatin remarkably enhanced the levels of mitochondrial apoptosis-related pathway proteins. Conclusion: Sodium butyrate, a histone acetylation inhibitor produced by intestinal flora fermentation, combined with cisplatin enhanced the apoptosis of GC cells through the mitochondrial apoptosis-related pathway, which might be considered as a therapeutic option for GC.

Keywords:  apoptosis; cisplatin; gastric cancer; mitochondrial pathway; sodium butyrate

DOI:  https://doi.org/10.3389/fphar.2021.708093
Aging (Albany NY). 2021 Sep 12. 13(undefined):

2,5-dimethyl celecoxib induces apoptosis and autophagy via activation of ROS/JNK axis in nasopharyngeal carcinoma cells.

Tan Tan, Xiangjie Fu, Jiaquan Qu, Miao Zhang, He Chen, Yaochun Wang, Bo Wang, Juan Li, Jie Liu, Peijun Liu.

  2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.

Keywords:  2,5-dimethyl celecoxib; apoptosis; autophagy; nasopharyngeal carcinoma

DOI:  https://doi.org/10.18632/aging.203488
Int J Med Sci. 2021 ;18(15): 3452-3462

Areca nut extract (ANE) inhibits the progression of hepatocellular carcinoma cells via activation of ROS production and activation of autophagy.

Po-Li Wei, Chin-Sheng Hung, Hsuan-Hsuan Lu, Uyanga Batzorig, Chien-Yu Huang, Yu-Jia Chang.

  Hepatocellular carcinoma (HCC) is a worldwide health problem. Currently, there is no effective therapeutic strategy for HCC patients. Chewing areca nut is closely associated with oral cancer and liver cirrhosis. The therapeutic effect of areca nut extract (ANE) on HCC is unknown. Our results revealed that ANE treatment caused a reduction in cell viability and an increase in cell apoptosis and suppressed tumor progression in xenograft models. ANE-treated didn't induce liver tumor in nude mice. For mechanism dissection, ANE treatment caused ROS-mediated autophagy and lysosome formation. Pretreatment with an ROS inhibitor, aminoguanidine hemisulfate (AGH), abolished ANE-induced ROS production. ANE treated cells caused an increase in light chain 3 (LC3)-I to -II conversion, anti-thymocyte globulin 5+12 (ATG5+12), and beclin levels, and apoptosis related-protein changes (an increases in BAX, cleaved poly(ADP-ribose) polymerase (c-PARP), and a decrease in the Bcl-2 level). In conclusion, our study demonstrated that the ANE may be a new potential compound for HCC therapy.

Keywords:  ANE; ROS; apoptosis; autophagy; hepatocellular carcinoma; lysosome

DOI:  https://doi.org/10.7150/ijms.61570
Int J Nanomedicine. 2021 ;16 6035-6048

Elemene Nanoemulsion Inhibits Metastasis of Breast Cancer by ROS Scavenging.

Bo Han, Tao Wang, Zhigang Xue, Tao Wen, Ling Lu, Jie Meng, Jian Liu, Sizhu Wu, Jianchun Yu, Haiyan Xu.

   Introduction: Elemene (C15H24) is a sesquiterpene compound extracted from the rhizome of Curcuma herbs. In the past decades, the anti-tumor activity of elemene has been observed in vitro and in some clinical practices. However, pharmacological mechanisms of elemene are not demonstrated adequately, which may lead to improper clinical applications. This study aimed to investigate the anti-tumor effect of elemene nanoemulsion in the mouse model of triple-negative breast cancer (TNBC) and reveal the underlying mechanisms.
Methods: The ESR measurement and quantum mechanics simulation were used to characterize the antioxidant ability of elemene nanoemulsion. The murine breast cancer cell line 4T1 cells were inoculated subcutaneously into the left fourth mammary fat pad of BalB/c mice to establish a TNBC mice model. The H&E staining, immunohistochemical staining, DHE staining and Western blot were employed to evaluate the therapeutic effects of the elemene nanoemulsion on the TNBC mice.
Results: It was shown that the elemene nanoemulsion prolonged the survival of the triple-negative breast cancer-bearing mice and inhibited the metastasis to lung and liver while did not induce significant cytotoxicity to the tumor cells. Mechanistic studies demonstrated that the elemene nanoemulsion effectively scavenged the reactive oxygen species (ROS) in vitro and in vivo, which decreased the stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently reduced angiogenesis in the tumor microenvironment as well as decreased the level of NLRP3 inflammasomes and IL-1β production. In addition, the elemene nanoemulsion downregulated the level of IL-1β in the RAW264.7 cells in exposure with LPS.
Conclusion: In conclusion, due to the ROS scavenging ability, elemene nanoemulsion effectively inhibited the metastasis of the breast cancer cells to lung and liver and consequently prolonged the survival of TNBC mice.

Keywords:  ROS; breast cancer; elemene; macrophages; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S327094
Anticancer Drugs. 2021 Sep 13.

Selective synergistic anticancer effects of cisplatin and oridonin against human p53-mutant esophageal squamous carcinoma cells.

Huiyu Yang, Jie Wang, Suliman Khan, Yuanying Zhang, Kuicheng Zhu, Enhui Zhou, Meiyuan Gong, Bingrong Liu, Quancheng Kan, Qi Zhang.

Oridonin (ORI) is known to pose anticancer activity against cancer, which could induce the therapeutic impact of chemotherapy drugs. However, such simple combinations have numerous side effects such as higher toxicity to normal cells and tissues. To enhance the therapeutic effects with minimal side effects, here we used ORI in combination with cisplitin (CIS) against different esophageal squamous cell carcinoma (ESCC) cell lines in vitro, to investigate the synergistic anticancer effects of the two drugs against ESCC. Calcusyn Graphing Software was used to assess the synergistic effect. Apoptosis, wound healing and cell invasion assay were conducted to further confirm the synergistic effects of ORI and CIS. Intracellular glutathione (GSH) and reactive oxygen species assay, immunofluorescence staining and western blot were used to verify the mechanism of synergistic cytotoxicity. ORI and CIS pose selective synergistic effects on ESCC cells with p53 mutations. Moreover, we found that the synergistic effects of these drugs are mediated by GSH/ROS systems, such that intracellular GSH production was inhibited, whereas the ROS generation was induced following ORI and CIS application. In addition, we noted that DNA damage was induced as in response to ORI and CIS treatment. Overall, these results suggest that ORI can synergistically enhance the effect of CIS, and GSH deficiency and p53 mutation, might be biomarkers for the combinational usage of ORI and CIS.

DOI: https://doi.org/10.1097/CAD.0000000000001237
Life Sci. 2021 Sep 14. pii: S0024-3205(21)00945-0. [Epub ahead of print] 119958

Cashing in on ferroptosis against tumor cells: Usher in the next chapter.

Mehdi Rabiee Valashedi, Nima Najafi-Ghalehlou, Amirsadegh Nikoo, Chia Bamshad, Kazuo Tomita, Yoshikazu Kuwahara, Tomoaki Sato, Amaneh Mohammadi Roushandeh, Mehryar Habibi Roudkenar.

  Ferroptosis is a new type of non-apoptotic regulated cell death (RCD) driven by unrestricted lethal lipid peroxidation, which is totally distinct from other forms of RCD in genetic and biochemical characteristics. It is generally believed that iron dependency, malfunction of the redox system, and excessive lipid peroxidation are the main hallmarks of ferroptosis. Accumulating pieces of evidence over the past few years have shown that ferroptosis is tightly related to various types of diseases, especially cancers. Ferroptosis has recently attracted great attention in the field of cancer research. A plethora of evidence shows that employing ferroptosis as a powerful weapon can remarkably enhance the efficacy of tumor cell annihilation. Better knowledge of the ferroptosis mechanisms and their interplay with cancer biology would enable us to use this fashionable tool in the best way. Herein, we will briefly present the relevant mechanisms of ferroptosis, the multifaceted relation between ferroptosis and cancer, encompassing tumor immunity, overcoming chemoresistance, and epithelial to mesenchymal transition. In the end, we will also briefly discuss the potential approaches to ferroptosis-based cancer therapy, such as using drugs and small molecules, nanoparticles, mitochondrial targeting, and photodynamic therapy.

Keywords:  Cancer therapy; Chemoresistance; Ferroptosis; Oxidative stress; Tumor immunity

DOI:  https://doi.org/10.1016/j.lfs.2021.119958
Free Radic Biol Med. 2021 Sep 11. pii: S0891-5849(21)00720-6. [Epub ahead of print]

PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells.

Gabriele Bluemel, Mélanie Planque, Corina T Madreiter-Sokolowski, Theresa Haitzmann, Andelko Hrzenjak, Wolfgang F Graier, Sarah-Maria Fendt, Horst Olschewski, Katharina Leithner.

  Cancer cells frequently lack nutrients like glucose, due to insufficient vascular networks. Mitochondrial phosphoenolpyruvate carboxykinase, PCK2, has recently been found to mediate partial gluconeogenesis and hence anabolic metabolism in glucose starved cancer cells. Here we show that PCK2 acts as a regulator of mitochondrial respiration and maintains the redox balance in nutrient-deprived human lung cancer cells. PCK2 silencing increased the abundance and interconversion of tricarboxylic acid (TCA) cycle intermediates, augmented mitochondrial respiration and enhanced glutathione oxidation under glucose and serum starvation, in a PCK2 re-expression reversible manner. Moreover, enhancing the TCA cycle by PCK2 inhibition severely reduced colony formation of lung cancer cells under starvation. As a conclusion, PCK2 contributes to maintaining a reduced glutathione pool in starved cancer cells besides mediating the biosynthesis of gluconeogenic/glycolytic intermediates. The study sheds light on adaptive responses in cancer cells to nutrient deprivation and shows that PCK2 confers protection against respiration-induced oxidative stress.

Keywords:  Adaptation; Cancer metabolism; Gluconeogenesis; Metabolic flexibility; Mitochondria; Redox balance; Respiration

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.09.007
Front Oncol. 2021 ;11 727605

Transferrin-Conjugated Erianin-Loaded Liposomes Suppress the Growth of Liver Cancer by Modulating Oxidative Stress.

Anhui Yang, Zhen Sun, Rui Liu, Xin Liu, Yue Zhang, Yulin Zhou, Ye Qiu, Xinrui Zhang.

   Background: Liver cancer is one of the most malignant human cancers, with few treatments and a poor prognosis. Erianin (ERN) is a natural compound with multiple pharmacological activities that has been reported to have numerous excellent effects against liver cancer in experimental systems. However, its application in vivo has been limited due to its poor aqueous solubility and numerous off-target effects. This study aimed to improve the therapeutic efficacy of ERN by developing novel ERN-loaded tumor-targeting nanoparticles.
Results: In this study, ERN was loaded into liposomes by ethanol injection (LP-ERN), and the resulting LP-ERN nanoparticles were treated with transferrin to form Tf-LP-ERN to improve the solubility and enhance the tumor-targeting of ERN. LP-ERN and Tf-LP-ERN nanoparticles had smooth surfaces and a uniform particle size, with particle diameters of 62.60 nm and 88.63 nm, respectively. In HepG2 and SMMC-7721 cells, Tf-LP-ERN induced apoptosis, decreased mitochondrial membrane potentials and increased ERN uptake more effectively than free ERN and LP-ERN. In xenotransplanted mice, Tf-LP-ERN inhibited tumor growth, but had a minimal effect on body weight and organ morphology. In addition, Tf-LP-ERN nanoparticles targeted tumors more effectively than free ERN and LP-ERN nanoparticles, and in tumor tissues Tf-LP-ERN nanoparticles promoted the cleavage PARP-1, caspase-3 and caspase-9, increased the expression levels of Bax, Bad, PUMA, and reduced the expression level of Bcl-2. Moreover, in the spleen of heterotopic tumor model BALB/c mice, ERN, LP-ERN and Tf-LP-ERN nanoparticles increased the expression levels of Nrf2, HO-1, SOD-1 and SOD-2, but reduced the expression levels of P-IKKα+β and P-NF-κB, with Tf-LP-ERN nanoparticles being most effective in this regard. Tf-LP-ERN nanoparticles also regulated the expression levels of TNF-α, IL-10 and CCL11 in serum.
Conclusion: Tf-LP-ERN nanoparticles exhibited excellent anti-liver cancer activity in vivo and in vitro by inducing cellular apoptosis, exhibiting immunoregulatory actions, and targeting tumor tissues, and did so more effectively than free ERN and LP-ERN nanoparticles. These results suggest that the clinical utility of a Tf-conjugated LP ERN-delivery system for the treatment of liver cancer warrants exploration.

Keywords:  apoptosis; erianin; liver cancer; mitochondrial; oxidative stress; transferrin-conjugated liposomes

DOI:  https://doi.org/10.3389/fonc.2021.727605
Redox Biol. 2021 Sep 09. pii: S2213-2317(21)00289-5. [Epub ahead of print]46 102130

Identification of peroxiredoxin 6 as a direct target of withangulatin A by quantitative chemical proteomics in non-small cell lung cancer.

Chen Chen, Lijie Gong, Xiaoqin Liu, Tianyu Zhu, Wuxi Zhou, Lingyi Kong, Jianguang Luo.

  Peroxiredoxin 6 (PRDX6), as a bifunctional enzyme with glutathione peroxidase activity (GPx) and Ca2+-independent phospholipase A2 (iPLA2) activity, has a higher expression in various cancer cells, which leads to the increase of antioxidant properties and promotes tumorigenesis. However, only a few inhibitors of PRDX6 have been discovered to date, especially the covalent inhibitors of PRDX6. Here, we firstly identified Withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PRDX6. SILAC-ABPP identified that WA could directly bind to PRDX6 and inactivate the enzyme activity of PRDX6 by the α, β-unsaturated ketone moiety. Moreover, WA also facilitated the generation of ROS, and inhibited the GPx and iPLA2 activities. However, WA-1, with a reduced α, β-unsaturated ketone moiety, had no significant inhibition of the GPx and iPLA2 activities. Biolayer interferometry and LC-MS/MS analysis further demonstrated the selectively covalent binding of WA to the cysteine 47 residue (Cys47) of PRDX6, while mutation of Cys47 blocked the binding of WA to PRDX6. Notably, WA-mediated cytotoxicity and inhibition of the GPx and iPLA2 activities were almost abolished by the deficiency of PRDX6. Therefore, this study indicates that WA is a novel PRDX6 covalent inhibitor, which could covalently bind to the Cys47 of PRDX6 and holds great potential in developing anti-tumor agents for targeting PRDX6.

Keywords:  Covalent inhibitor; Non-small cell lung cancer; Oxidative stress; Peroxiredoxin 6; Withangulatin A

DOI:  https://doi.org/10.1016/j.redox.2021.102130