bims-rehoca 2021-08-22 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021‒08‒22
twenty-two papers selected by
Vittoria Raimondi
Veneto Institute of Oncology

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy.
Tumor Microenvironment-Responsive Nanozymes Achieve Photothermal-Enhanced Multiple Catalysis Against Tumor Hypoxia.
Anticancer Effect of ERM210 on Liver Cancer Cells Through ROS/Mitochondria-dependent Apoptosis Signaling Pathways.
Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells.
Folic acid-modified ROS-responsive nanoparticles encapsulating luteolin for targeted breast cancer treatment.
Fucoxanthin induced apoptotic cell death in oral squamous carcinoma (KB) cells.
Plasma-activated thermosensitive biogel as an exogenous ROS carrier for post-surgical treatment of cancer.
The Involvement of the Oxidative Stress Status in Cancer Pathology: A Double View on the Role of the Antioxidants.
Loss of pro-apoptotic Bax and Bak increases resistance to dihydroartemisinin-mediated cytotoxicity in normoxia but not in hypoxia in HCT116 colorectal cancer cells.
Autophagy induced by H. pylori VacA regulated the survival mechanism of the SGC7901 human gastric cancer cell line.
Cytotoxic Activity of Isoniazid Derivative in Human Breast Cancer Cells.
Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-κB Signal Transduction Pathways in Colon Cancer Cells.
Controlled killing of human cervical cancer cells by combined action of blue light and C-doped TiO2 nanoparticles.
MoO3-x nanosheets-based platform for single NIR laser induced efficient PDT/PTT of cancer.
Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer.
Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells.
Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation.
Ruthenium(II) complexes coordinated to graphitic carbon nitride: Oxygen self-sufficient photosensitizers which produce multiple ROS for photodynamic therapy in hypoxia.
Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy.
Oxidative stress in leukemia and antioxidant treatment.
Antiproliferative effects of Turkish pomegranate (Punica granatum L.) extracts on MCF-7 human breast cancer cell lines with focus on antioxidant potential and bioactive compounds analyzed by LC-MS/MS.
D-carvone induced ROS mediated apoptotic cell death in human leukemic cell lines (Molt-4).

J Cancer. 2021 ;12(18): 5543-5561

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy.

Run Huang, Huan Chen, Jiayu Liang, Yi Li, Jiali Yang, Chuang Luo, Youshan Tang, Yu Ding, Xing Liu, Qing Yuan, Hong Yu, Yingchun Ye, Wenfeng Xu, Xiang Xie.

  Reactive oxygen species (ROS) play a dual role in the initiation, development, suppression, and treatment of cancer. Excess ROS can induce nuclear DNA, leading to cancer initiation. Not only that, but ROS also inhibit T cells and natural killer cells and promote the recruitment and M2 polarization of macrophages; consequently, cancer cells escape immune surveillance and immune defense. Furthermore, ROS promote tumor invasion and metastasis by triggering epithelial-mesenchymal transition in tumor cells. Interestingly, massive accumulation of ROS inhibits tumor growth in two ways: (1) by blocking cancer cell proliferation by suppressing the proliferation signaling pathway, cell cycle, and the biosynthesis of nucleotides and ATP and (2) by inducing cancer cell death via activating endoplasmic reticulum stress-, mitochondrial-, and P53- apoptotic pathways and the ferroptosis pathway. Unfortunately, cancer cells can adapt to ROS via a self-adaption system. This review highlighted the bidirectional regulation of ROS in cancer. The study further discussed the application of massively accumulated ROS in cancer treatment. Of note, the dual role of ROS in cancer and the self-adaptive ability of cancer cells should be taken into consideration for cancer prevention.

Keywords:  anti-cancer; cancer; pro-tumor; reactive oxygen species; self-adaption system; therapy

DOI:  https://doi.org/10.7150/jca.54699
Acta Biomater. 2021 Aug 15. pii: S1742-7061(21)00541-9. [Epub ahead of print]

Tumor Microenvironment-Responsive Nanozymes Achieve Photothermal-Enhanced Multiple Catalysis Against Tumor Hypoxia.

Wenjia Lv, Mengzhu Cao, Jingju Liu, Yashuang Hei, Jing Bai.

  Reactive oxygen species (ROS)-mediated antitumor modalities that induced oxidative damage of cancer cells have recently acquired increasing attention on account of their noninvasiveness, low systemic toxicity, and high specificity. However, their clinical efficacy was often constrained by complex and various tumor microenvironment (TME), especially hypoxia characteristic and antioxidation effect of glutathione (GSH). Herein, we constructed a multinanozyme system based on hyaluronic acid (HA)-stabilized CuMnOx nanoparticles (CMOH) loaded with indocyanine green (ICG) with high-efficient ROS generation, O2 self-evolving function, GSH depletion ability and hyperthermia effect for achieving hypoxic tumor therapy. The CMOH nanozymes exhibited peroxidase-like and oxidase-like activities, which could efficiently catalyze H2O2 or O2 to generate hydroxyl radicals (•OH) or superoxide radicals (•O2-) in acidic tumor microenvironment (TME), elevating oxidative stress of tumor. Indocyanine green (ICG) was further loaded into HA-CuMnOx to form HA-CuMnOx@ICG nanocomposites (CMOI NCs), which can effectively generate singlet oxygen (1O2) and local hyperthermia under light irradiation. The hyperthermia generated by CMOI NCs further enhances the catalytic activities of nanozymes for ROS generation. Meanwhile, the CMOI with catalase-like activity could catalyze H2O2 into O2 for relieving tumor hypoxia and elevate O2-dependent ROS generation. Notably, CMOI can consume endogenous GSH, thereby impairing tumor antioxidant system and enhancing ROS-based therapy efficacy. After modified with HA, CMOI NCs with tumor targeting ability realized synergistic PTT-enhanced tumor oxidation therapy based on their multimodal properties. Thus, this work contributes to design high-performance therapeutic reagent to overcome the limitation of hypoxia and high antioxidant defense of tumor. STATEMENT OF SIGNIFICANCE: Reactive oxygen species (ROS)-mediated antitumor modalities were often constrained by complex and various tumor microenvironment (TME), especially hypoxia characteristic and antioxidation effect of glutathione (GSH). In this work, a multinanozyme system based on hyaluronic acid (HA)-stabilized CuMnOx nanoparticles (CMOH) loaded with indocyanine green (ICG) was designed to realize PTT-enhanced multiple catalysis tumor therapy. Although antitumor modalities based on multienzyme catalysis have been developed. Here, we highlighted the responsive catalysis of multienzyme system on tumor microenvironment (TME) and the promoting effect of photothermal effect on ROS production. Both in vitro and in vivo manifested that the enhanced anticancer efficacy of CMOI NCs due to their thermally amplified catalytic activity and TME regulation ability.

Keywords:  GSH depletion; Nanozyme catalysis; Reactive oxygen species; Synergistic treatment; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.actbio.2021.08.015
In Vivo. 2021 Sep-Oct;35(5):35(5): 2599-2608

Anticancer Effect of ERM210 on Liver Cancer Cells Through ROS/Mitochondria-dependent Apoptosis Signaling Pathways.

Jaihyung Lee, Yi-Xi Gong, Dan-Ping Xie, Hyunjeong Jeong, Hoyoung Seo, Jihwan Kim, Yang Ho Park, Hu-Nan Sun, Taeho Kwon.

  BACKGROUND/AIM: Asian Traditional medicines are renowned for their antitumor properties and are efficacious in the clinical treatment of various cancer types. ERM210 is a Korean traditional medicine comprising nine types of medicinal plants. In the present study, we examined the pro-apoptotic effect and molecular mechanisms of the effects of ERM210 on HepG2 liver cancer cells.MATERIALS AND METHODS: The cytotoxicity of ERM210 on HepG2 cells was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays, and apoptosis and signaling pathways by fluorescence microscopy flow cytometry and western blotting.
RESULTS: ERM210 significantly impaired HepG2 cell viability and enhanced mitochondria-dependent cellular apoptosis in a time- and dose-dependent manner by up-regulating the expression of caspases 3, 7 and 9, and of BCL2 apoptosis regulator (BCL2)-associated X, apoptosis regulator (BAX) proteins, whilst down-regulating that of BCL2 protein. Furthermore, ERM210 treatment increased accumulation of cellular and mitochondrial reactive oxygen species (ROS) and significantly inhibited cell migration. Additionally, all these phenomena were reversed by treating with the ROS scavenger N-acetylcysteine. The analysis of signaling proteins revealed that ERM210 significantly up-regulated the phosphorylation of ROS-dependent mitogen-activated protein kinases (p38, extracellular-regulated kinase, and c-Jun N-terminal kinase in HepG2 liver cancer cells.
CONCLUSION: ERM210 exerts anticancer effects in HepG2 liver cancer cells by up-regulating ROS/mitochondria-dependent apoptosis signaling, providing new insight into the possibility of employing this traditional medicine for the clinical treatment of liver cancer.

Keywords:  Anticancer; ERM210; apoptosis; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.21873/invivo.12542
Front Pharmacol. 2021 ;12 673103

Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells.

Shoaib Shoaib, Saba Tufail, Mohammad Asif Sherwani, Nabiha Yusuf, Najmul Islam.

  The latest research shows that current chemotherapeutics are ineffective because of the development of resistance in cervical cancer cells, and hence, their scope of use is limited. The main concern of researchers at the moment is the discovery of safe and effective antiproliferative plant chemicals that can aid in the battle against cervical cancer. Previous studies have shown the possible anticancer potential of phenethyl isothiocyanate obtained from cruciferous plants for many cancers, which targets various signaling pathways to exercise chemopreventive and therapeutic effects. This provides the basis for studying phenethyl isothiocyanate's therapeutic potential against cervical cancer. In the present study, cervical cancer cells were treated with various doses of phenethyl isothiocyanate, alone and in combination with cisplatin. Phenethyl isothiocyanate alone was sufficient to cause nucleus condensation and fragmentation and induce apoptosis in cervical cancer cells, but evident synergistic effects were observed in combination with cisplatin. In addition, phenethyl isothiocyanate treatment increased the production of intracellular ROS in a dose-dependent manner in cervical cancer cells. Furthermore, investigation of phenethyl isothiocyanate induced mitochondrial reactive oxygen species production, and activation of caspases showed that phenethyl isothiocyanate significantly activated caspase-3.

Keywords:  DNA fragmentation; HPV16+; ROS; apoptosis; cervical cancer

DOI:  https://doi.org/10.3389/fphar.2021.673103
Drug Deliv. 2021 Dec;28(1): 1695-1708

Folic acid-modified ROS-responsive nanoparticles encapsulating luteolin for targeted breast cancer treatment.

Yu Wang, Qianmei Wang, Wei Feng, Qian Yuan, Xiaowei Qi, Sheng Chen, Pu Yao, Qing Dai, Peiyuan Xia, Dinglin Zhang, Fengjun Sun.

  Luteolin (Lut) is a natural flavonoid polyphenolic compound with multiple pharmacological activities, such as anti-oxidant, anti-inflammatory, and anti-tumor effects. However, the poor aqueous solubility and low bioactivity of Lut restrict its clinical translation. Herein, we developed a reactive oxygen species (ROS)-responsive nanoplatforms to improve the bioactivity of Lut. Folic acid (FA) was employed to decorate the nanoparticles (NPs) to enhance its targeting ability. The size of Lut-loaded ROS-responsive nanoparticles (Lut/Oxi-αCD NPs) and FA-modified Lut/Oxi-αCD NPs (Lut/FA-Oxi-αCD NPs) is 210.5 ± 6.1 and 196.7 ± 1.8 nm, respectively. Both Lut/Oxi-αCD NPs and Lut/FA-Oxi-αCD NPs have high drug loading (14.83 ± 3.50 and 16.37 ± 1.47%, respectively). In vitro cellular assays verified that these NPs could be efficiently internalized by 4T1 cells and the released Lut from NPs could inhibit tumor cells proliferation significantly. Animal experiments demonstrated that Lut/Oxi-αCD NPs, especially Lut/FA-Oxi-αCD NPs obviously accumulated at tumor sites, and inhibited tumor growth ∼3 times compared to the Lut group. In conclusion, the antitumor efficacy of Lut was dramatically improved by targeting delivery with the ROS-responsive nanoplatforms.

Keywords:  Luteolin; breast cancer; nanoparticles; reactive oxygen species; targeting therapy

DOI:  https://doi.org/10.1080/10717544.2021.1963351
Bioinformation. 2021 ;17(1): 181-191

Fucoxanthin induced apoptotic cell death in oral squamous carcinoma (KB) cells.

Petchi Iyappan, M Devi Bala, M Sureshkumar, Vishnu Priya Veeraraghavan, Arulselvan Palanisamy.

  Fucoxanthin (Fx) is an active compound commonly found in the many types of seaweed with numerous biological activities. The main goal of this investigation is to explore the effect of Fx against the cell proliferation, apoptotic induction and oxidative stress in the oral squamous (KB) cell line. Cytotoxicity of Fx was determined by MTT assay. The intracellular ROS production, mitochondrial membrane potential (MMP) and apoptosis induction in KB cells were examined through DCFH-DA, Rhodamine-123 and DAPI, and dual staining techniques. Effect of Fx on the antioxidant enzymes and lipid peroxidation in the KB cells was studied through the standard procedures. Fx treated KB cells showed morphological changes and reduced cell survival, which is exhibited by the cytotoxic activity of 50 µM/ml (IC50) Fx against the KB cells. The Fx treatment considerably induced the apoptotosis cells (EB/AO) and decreased the MMP (Rh-123) in KB cells. Further, it was pointed out that there was an increased lipid peroxidation (LPO) with decreased antioxidants (CAT, SOD and GSH). These results concluded that Fx has the cytotoxic effect against KB cells and has the potential to induce the apoptosis via increased oxidative stress. Hence, the Fx can be a promising agent for the treatment of oral cancer and it may lead to the development of cancer therapeutics.

Keywords:  Antioxidant; Cytotoxicity; Lipid peroxidation; Oral cancer; Reactive oxygen species

DOI:  https://doi.org/10.6026/97320630017181
Biomaterials. 2021 Aug 09. pii: S0142-9612(21)00413-0. [Epub ahead of print]276 121057

Plasma-activated thermosensitive biogel as an exogenous ROS carrier for post-surgical treatment of cancer.

Hao Zhang, Shengduo Xu, Jishen Zhang, Zifeng Wang, Dingxin Liu, Li Guo, Cheng Cheng, Yilong Cheng, Dehui Xu, Michael G Kong, Mingzhe Rong, Paul K Chu.

  Post-surgical residual tumor cells are the primary cause of relapse and progression of cancer but unfortunately, there are limited therapeutic options. In this work, a fillable plasma-activated biogel is produced on a thermosensitive biogel [(Poly-DL-lactide)-(poly-ethylene glycol)-(poly-DL-lactide), PLEL] with the aid of a discharge plasma for local post-operative treatment of cancer. In vivo data show that the plasma-activated PLEL biogel (PAPB) eliminates residual tumor tissues after removal surgery and also inhibits in situ recurrence while showing no evident systemic toxicity. Moreover, the PAPB possesses excellent storage capability, allows for slow release of plasma-generated reactive oxygen species (ROS), and exhibits good ROS-mediated anticancer effects in vitro. Our results reveal that the novel plasma-activated biogel is an effective therapeutic agent for local post-operative treatment of cancer.

Keywords:  Plasma-activated biogel; Post-operative tumor treatment; Reactive oxygen species; Surface discharge plasma

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121057
Oxid Med Cell Longev. 2021 ;2021 9965916

The Involvement of the Oxidative Stress Status in Cancer Pathology: A Double View on the Role of the Antioxidants.

Kamal Fatima Zahra, Radu Lefter, Ahmad Ali, Ech-Chahad Abdellah, Constantin Trus, Alin Ciobica, Daniel Timofte.

Oxygen-free radicals, reactive oxygen species (ROS) or reactive nitrogen species (RNS), are known by their "double-sided" nature in biological systems. The beneficial effects of ROS involve physiological roles as weapons in the arsenal of the immune system (destroying bacteria within phagocytic cells) and role in programmed cell death (apoptosis). On the other hand, the redox imbalance in favor of the prooxidants results in an overproduction of the ROS/RNS leading to oxidative stress. This imbalance can, therefore, be related to oncogenic stimulation. High levels of ROS disrupt cellular processes by nonspecifically attacking proteins, lipids, and DNA. It appears that DNA damage is the key player in cancer initiation and the formation of 8-OH-G, a potential biomarker for carcinogenesis. The harmful effect of ROS is neutralized by an antioxidant protection treatment as they convert ROS into less reactive species. However, contradictory epidemiological results show that supplementation above physiological doses recommended for antioxidants and taken over a long period can lead to harmful effects and even increase the risk of cancer. Thus, we are describing here some of the latest updates on the involvement of oxidative stress in cancer pathology and a double view on the role of the antioxidants in this context and how this could be relevant in the management and pathology of cancer.

DOI: https://doi.org/10.1155/2021/9965916
Free Radic Biol Med. 2021 Aug 14. pii: S0891-5849(21)00471-8. [Epub ahead of print]174 157-170

Loss of pro-apoptotic Bax and Bak increases resistance to dihydroartemisinin-mediated cytotoxicity in normoxia but not in hypoxia in HCT116 colorectal cancer cells.

Sina Bader, Julia Wilmers, Teona Ontikatze, Violetta Ritter, Verena Jendrossek, Justine Rudner.

  Tumor hypoxia is a major biological factor that drives resistance to chemotherapy and radiotherapy. We previously demonstrated that the pro-oxidative drug dihydroartemisinin (DHA) efficiently targeted normoxic and hypoxic cancer cells. Although well studied in normoxia, the mechanism behind DHA-mediated cytotoxicity in hypoxia is insufficiently explored. Here, we analyzed the effect of DHA in HCT116 wild type (wt) cells and in HCT116 Bax-/-Baksh cells with a defective intrinsic apoptosis pathway. Normoxic HCT116 wt cells underwent apoptosis shortly after treatment with DHA. Autophagy-associated cell death contributes to short-term cytotoxicity of DHA in normoxia. These cells switched to an apoptosis- and autophagy-independent cell death after treatment with DHA in hypoxia and displayed similar long-term survival in response to DHA in normoxia and hypoxia. In HCT116 Bax-/-Baksh cells, DHA induced cell cycle arrest shortly after treatment irrespective of oxygen levels. Later, HCT116 Bax-/-Baksh cells induced a delayed cell death after treatment with DHA in hypoxia followed by return to normoxia, while treatment with DHA in normoxia was hardly toxic. We identified lower glutathione levels in hypoxic HCT116 cells which correlated with higher lipid peroxidation after treatment with DHA. Moreover, insufficient expression of Bax/Bak counteracted hypoxia-mediated downregulation of mitochondrial function, thereby adding to DHA-induced ROS production and lipid peroxidation in hypoxia. In summary, DHA-mediated cytotoxicity in normoxia depended on Bax/Bak expression, while cytotoxicity after treatment with DHA in hypoxia was regulated independently of Bax/Bak in HCT116 colorectal cancer cells.

Keywords:  Apoptosis; Dihydroartemisinin; Glutathione; Hypoxia; Lipid peroxidation; Reactive oxygen species; Therapy resistance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.08.012
Genes Genomics. 2021 Aug 16.

Autophagy induced by H. pylori VacA regulated the survival mechanism of the SGC7901 human gastric cancer cell line.

Juan Luo, Luyan Bai, Jun Tao, Yu Wen, Mingke Li, Yunzhen Zhu, Sufeng Luo, Guangyu Pu, Lanqing Ma.

  BACKGROUND: Vacuolating cytotoxin (VacA) is an important virulence factor of Helicobacter pylori (H. pylori). It was previously believed that VacA can trigger the cascade of apoptosis on mitochondria to lead to cell apoptosis. Recently, it was found that VacA can induce autophagy. However, the molecular mechanism by which VacA induces autophagy is largely unknown.OBJECTIVE: We aimed to explore the molecular mechanism of autophagy induced by H. pylori in gastric cancer cells and the effect of autophagy on the survival of gastric cancer cells.
METHODS: The autophagy of human gastric cancer cell line SGC7901 was detected by Western blot and RT-PCR in the treatment of VacA protein of H. pylori. The relationship between autophagy and reactive oxygen species (ROS) in the proliferation of gastric cancer cells were studied by gene expression silences (siRNA) and CM-H2DCFDA (DCF) staining.
RESULTS: The results showed that VacA protein secreted by H. pylori in the supernatant stimulated autophagy in SGC7901 cells. After VacA protein treatment, the mRNA expressions of BECN1, ATG7 and PIK3C3, were up-regulated. ATG7 silencing by siRNA inhibited VacA-induced autophagy. Furthermore, our data demonstrated that VacA protein increased ROS levels. Addition of the antioxidant N-acetyl-L-cysteine (NAC) suppressed the levels of ROS, leading to inhibition of autophagy.
CONCLUSIONS: H. pylori VacA is a key toxin that induces autophagy by increased ROS levels. And our findings demonstrated that VacA significantly inhibited proliferation in SGC7901 cells.

Keywords:  Autophagy; Helicobacter pylori; Reactive oxygen species; Vacuolating cytotoxin

DOI:  https://doi.org/10.1007/s13258-021-01151-7
In Vivo. 2021 Sep-Oct;35(5):35(5): 2675-2685

Cytotoxic Activity of Isoniazid Derivative in Human Breast Cancer Cells.

Muttiah Barathan, Ahmad Khusairy Zulpa, Kumutha Malar Vellasamy, Vanitha Mariappan, Naveen Kumar Hawala Shivashekaregowda, Zaridatul Aini Ibrahim, Jamuna Vadivelu.

  BACKGROUND/AIM: Isoniazid is an antibiotic used for the treatment of tuberculosis. Previously, we found that the isoniazid derivative (E)-N'-(2,3,4-trihydroxybenzylidene) isonicotinohydrazide (ITHB4) could be developed as novel antimycobacterial agent by lead optimization. We further explored the ability of this compound compared to zerumbone in inhibiting the growth of MCF-7 breast cancer cells.MATERIALS AND METHODS: Cytotoxicity was measured by the MTT assay and further confirmed via apoptosis, ROS, cell cycle, DNA fragmentation and cytokine assays.
RESULTS: ITHB4 demonstrated a lower IC50 compared to zerumbone in inhibiting the proliferation of MCF-7 cells. ITHB4 showed no toxicity against normal breast and human immune cells. Apoptosis assay revealed that ITHB4, at a concentration equal to the IC50, induces apoptosis of MCF-7 cells and cell cycle arrest at the sub-G1 and G2/M phases. ITHB4 triggered accumulation of intracellular ROS and nuclear DNA fragmentation. Secretion of pro-inflammatory cytokines induced inflammation and potentially immunogenic cell death.
CONCLUSION: ITHB4 has almost similar chemotherapeutic properties as zerumbone in inhibiting MCF-7 growth, and hence provide the basis for further experiments in animal models.

Keywords:  Apoptosis; breast cancer cells; cytokine; isoniazid; reactive oxygen species; synthetic compound; zerumbone

DOI:  https://doi.org/10.21873/invivo.12551
Biomed Res Int. 2021 ;2021 1383878

Investigation of the Role of Neurokinin-1 Receptor Inhibition Using Aprepitant in the Apoptotic Cell Death through PI3K/Akt/NF-κB Signal Transduction Pathways in Colon Cancer Cells.

Atefeh Ghahremanloo, Hossein Javid, Amir R Afshari, Seyed Isaac Hashemy.

Background: Colorectal cancer (CRC) is recognized as one of the most common malignancies with a high mortality rate worldwide, supporting the necessity for an effective novel antitumor drug to improve current therapy's effectiveness. Substance P (SP) is the essential member of the tachykinins (TKs) family, which binds to the specific receptors, known as neurokinin-1 receptor (NK1R), exerting its multiple influences such as tumor cell proliferation, angiogenesis, and metastasis. Aprepitant, as a specific NK1R antagonist, is suggested as a novel antitumor agent, promoting apoptotic processes in tumor cells; however, the exact antitumor mechanism of aprepitant on molecular signaling in CRC is not entirely known.Method: The resazurin assay was conducted to assess the cytotoxic effects of aprepitant on the viability of the CRC cell line (SW480). The level of reactive oxygen species (ROS) was measured after 24-hour treatment with SP and aprepitant. PI/annexin V-FITC staining was conducted to assess apoptosis. Also, the expression of NF-κB antiapoptotic target genes and proapoptotic p53 target genes was measured by real-time- (RT-) PCR assay. Western blotting assay was performed to determine the expression of PI3k/AKT/NF-κB proteins.
Results: We found that aprepitant stimulates apoptotic cell death and attenuates the PI3K/Akt pathway and its downstream proapoptotic target gene, including NF-κB in SW480 cells. Also, the obtained results from the quantitative RT-PCR assay showed that aprepitant could decrease the level of mRNA of NF-κB antiapoptotic target genes.
Conclusion: Towards this end, this study suggests that SP/NK1R system plays a vital role in the development of CRC, and pharmaceutical targeting of NK1R using aprepitant might be a promising treatment against CRC.

DOI: https://doi.org/10.1155/2021/1383878
Photochem Photobiol Sci. 2021 Aug 16.

Controlled killing of human cervical cancer cells by combined action of blue light and C-doped TiO2 nanoparticles.

Milica Matijević, Jelena Žakula, Lela Korićanac, Marija Radoičić, Xinyue Liang, Lan Mi, Jelena Filipović Tričković, Ana Valenta Šobot, Maja N Stanković, Đura Nakarada, Miloš Mojović, Marijana Petković, Milutin Stepić, Maja D Nešić.

  In this study, C-doped TiO2 nanoparticles (C-TiO2) were prepared and tested as a photosensitizer for visible-light-driven photodynamic therapy against cervical cancer cells (HeLa). X-ray diffraction and Transmission Electron Microscopy confirmed the anatase form of nanoparticles, spherical shape, and size distribution from 5 to 15 nm. Ultraviolet-visible light spectroscopy showed that C doping of TiO2 enhances the optical absorption in the visible light range caused by a bandgap narrowing. The photo-cytotoxic activity of C-TiO2 was investigated in vitro against HeLa cells. The lack of dark cytotoxicity indicates good biocompatibility of C-TiO2. In contrast, a combination with blue light significantly reduced the survival of HeLa cells: illumination only decreased cell viability by 30% (15 min of illumination, 120 µW power), and 60% when HeLa cells were preincubated with C-TiO2. We have also confirmed blue light-induced C-TiO2-catalyzed generation of reactive oxygen species in vitro and intracellularly. Oxidative stress triggered by C-TiO2/blue light was the leading cause of HeLa cell death. Fluorescent labeling of treated HeLa cells showed distinct morphological changes after the C-TiO2/blue light treatment. Unlike blue light illumination, which caused the appearance of large necrotic cells with deformed nuclei, cytoplasm swelling, and membrane blebbing, a combination of C-TiO2/blue light leads to controlled cell death, thus providing a better outcome of local anticancer therapy.

Keywords:  Autophagy; Blue light; C-doped TiO2; HeLa; Photodynamic therapy; Reactive oxygen species

DOI:  https://doi.org/10.1007/s43630-021-00082-2
J Control Release. 2021 Aug 12. pii: S0168-3659(21)00428-4. [Epub ahead of print]

MoO3-x nanosheets-based platform for single NIR laser induced efficient PDT/PTT of cancer.

Fan Wu, Qicheng Zhang, Baohong Sun, Xiaohong Chu, Ming Zhang, Zhangcai She, Zihan Li, Ninglin Zhou, Jianxiu Wang, Ao Li.

  Traditional combination therapy of photodynamic therapy (PDT) and photothermal therapy (PTT) is limited in the field of clinical cancer therapy due to activation by light with separate wavelengths, insufficient O2 supply, antioxidant ability of glutathione (GSH) in tumor cell, and low penetration depth of light. Here, a multifunctional nanoplatform composed of MoO3-x nanosheets, Ag nanocubes, and MnO2 nanoparticles was developed to overcome these drawbacks. For this nanoplatform, hyperthermia and reactive oxygen species (ROS) were simultaneously generated under single 808 nm near-infrared (NIR) light irradiation. Once this nanoplatform accumulated in the tumor region, GSH was depleted by MnO2 and intracellular H2O2 was catalyzed by MnO2 to produce O2 to relieve hypoxia. Ultrasound (US) imaging confirmed in-situ O2 generation. Magnetic resonance (MR) imaging, photoacoustic (PA) imaging, and fluorescence imaging were used to monitor in vivo biodistribution of nanomaterials. This provides a paradigm to rationally design a single NIR laser induced multimodal imaging-guided efficient PDT/PTT cancer strategy.

Keywords:  In-situ O(2) generation; Multimodal imaging; Photodynamic therapy; Photothermal therapy; Single 808 nm NIR light

DOI:  https://doi.org/10.1016/j.jconrel.2021.08.022
J Exp Clin Cancer Res. 2021 Aug 19. 40(1): 260

Ethaselen synergizes with oxaliplatin in tumor growth inhibition by inducing ROS production and inhibiting TrxR1 activity in gastric cancer.

Haiyong Zhang, Jing Wu, Jinqiu Yuan, Huafu Li, Yawei Zhang, Wang Wu, Wei Chen, Chunming Wang, Sijun Meng, Songyao Chen, Mingyu Huo, Yulong He, Changhua Zhang.

  BACKGROUND: Oxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro.METHODS: Cellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect.
RESULTS: We found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis.
CONCLUSIONS: This study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.

Keywords:  Ethaselen; Gastric cancer; Organoids; Oxaliplatin; Reactive oxygen species; Thioredoxin reductase 1; Tumor growth inhibition

DOI:  https://doi.org/10.1186/s13046-021-02052-z
Biomed Pharmacother. 2021 Aug 16. pii: S0753-3322(21)00817-9. [Epub ahead of print]142 112034

Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells.

Ana Carolina B da C Rodrigues, Larissa M Bomfim, Sara P Neves, Milena B P Soares, Rosane B Dias, Ludmila F Valverde, Clarissa A Gurgel Rocha, Emmanoel V Costa, Felipe M A da Silva, Waldireny C Rocha, Hector H F Koolen, Daniel P Bezerra.

  Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin.

Keywords:  22-hydroxytingenone; AML; Apoptosis; Oxidative stress; Thioredoxin; Tingenone

DOI:  https://doi.org/10.1016/j.biopha.2021.112034
Clin Cancer Res. 2021 Aug 18. pii: clincanres.4789.2020. [Epub ahead of print]

Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation.

Avani Vyas, Richard A Harbison, Daniel L Faden, Mark Kubik, Drake Palmer, Qing Zhang, Hatice U Osmanbeyoglu, Umamaheswar Duvvuri, Eduardo Méndez.

PURPOSE: Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, ~10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear.EXPERIMENTAL DESIGN: We performed RNA seq on tissues from matched primary (pOPSCC) and metachronous recurrent cancers (rOPSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (1) NRF2 overexpression on growth in vitro and in vivo (2) OXPHOS inhibition using IACS-010759 on NRF2 dependent cells (3) combination of cisplatin and OXPHOS inhibition.
RESULTS: The oxidative phosphorylation (OXPHOS) pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from the Cancer Genome Atlas with enrichment in OXPHOS, fatty acid metabolism, Myc, Mtor, ROS, and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells.
CONCLUSIONS: These results unveil a paradigm shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-4789
Biomaterials. 2021 Aug 09. pii: S0142-9612(21)00420-8. [Epub ahead of print]276 121064

Ruthenium(II) complexes coordinated to graphitic carbon nitride: Oxygen self-sufficient photosensitizers which produce multiple ROS for photodynamic therapy in hypoxia.

Fangmian Wei, Shi Kuang, Thomas W Rees, Xinxing Liao, Jiangping Liu, Diqing Luo, Jinquan Wang, Xiting Zhang, Liangnian Ji, Hui Chao.

  The photodynamic therapy (PDT) of cancer is limited by tumor hypoxia as PDT efficiency depends on O2 concentration. A novel oxygen self-sufficient photosensitizer (Ru-g-C3N4) was therefore designed and synthesized via a facile one-pot method in order to overcome tumor hypoxia-induced PDT resistance. The photosensitizer is based on [Ru(bpy)2]2+ coordinated to g-C3N4 nanosheets by Ru-N bonding. Compared to pure g-C3N4, the resulting nanosheets exhibit increased water solubility, stronger visible light absorption, and enhanced biocompatibility. Once Ru-g-C3N4 is taken up by hypoxic tumor cells and exposed to visible light, the nanosheets not only catalyze the decomposition of H2O2 and H2O to generate O2, but also catalyze H2O2 and O2 concurrently to produce multiple ROS (•OH, •O2-, and 1O2). In addition, Ru-g-C3N4 affords luminescence imaging, while continuously generating O2 to alleviate hypoxia greatly improving PDT efficacy. To the best of our knowledge, this oxygen self-sufficient photosensitizer produced via grafting a metal complex onto g-C3N4 is the first of its type to be reported.

Keywords:  Graphite carbon nitride; Multiple ROS; Oxygen self-sufficient photosensitizers; Photodynamic therapy; Ruthenium

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121064
ACS Nano. 2021 Aug 20.

Dual Inhibition of Endoplasmic Reticulum Stress and Oxidation Stress Manipulates the Polarization of Macrophages under Hypoxia to Sensitize Immunotherapy.

Mengshi Jiang, Xiang Li, Junlei Zhang, Yichao Lu, Yingying Shi, Chunqi Zhu, Yu Liu, Bing Qin, Zhenyu Luo, Yongzhong Du, Lihua Luo, Ling Peng, Jian You.

  M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.

Keywords:  ER stress; anti-PD-1 immunotherapy; hypoxia; macrophages repolarization; oxidative stress

DOI:  https://doi.org/10.1021/acsnano.1c04068
Chin Med J (Engl). 2021 Jul 12. 134(16): 1897-1907

Oxidative stress in leukemia and antioxidant treatment.

Chao Dong, Nai-Jin Zhang, Li-Jun Zhang.

ABSTRACT: Oxidative stress is caused by the imbalance between the generation of free radicals/reactive oxygen species (ROS) and the antioxidant defense systems, which can activate various transcription factors and affect their transcriptional pathways. Oxidative stress plays an important role in the occurrence and development of leukemia and is closely related to the treatment and prognosis of leukemia. The standard chemotherapy strategies for the pre-treatment of leukemia have many drawbacks. Hence, the usage of antioxidants and oxidants in the treatment of leukemia is being explored and has been preliminarily applied. This article reviews the research progress of oxidative stress and leukemia. In addition, the application of antioxidants treatment in leukemia has been summarized.

DOI: https://doi.org/10.1097/CM9.0000000000001628
J Food Biochem. 2021 Aug 19. e13904

Antiproliferative effects of Turkish pomegranate (Punica granatum L.) extracts on MCF-7 human breast cancer cell lines with focus on antioxidant potential and bioactive compounds analyzed by LC-MS/MS.

Esra Eroglu Ozkan, Mehmet Fatih Seyhan, Ozlem Kurt Sirin, Tugba Yilmaz-Ozden, Ezgi Ersoy, Seda Damla Hatipoglu Cakmar, Ahmet Ceyhan Goren, Hulya Yilmaz Aydogan, Oguz Ozturk.

  In this study, eight different pomegranate (Punica granatum L.) cultivars from Turkey were evaluated for their antioxidant and cytotoxic effects on the MCF-7 breast cancer cell lines and MCF-10A breast fibrocystic epithelial cell lines with a focus on their chemical compositions by LC-MS/MS. Cell lines were treated with pomegranate juice extracts in different doses at selected time intervals (24th, 48th, and 72nd hour). Afterwards, WST-1 cell proliferation assay was performed to investigate the cytotoxicity of the extracts. Accordingly, all extracts decreased the cell viability of MCF-7 breast cancer cell lines and had no cytotoxic effect on the cell viability of MCF-10A cell lines. Among eight extracts, P7 (Izmir 1513), which was rich in anthocyanins such as cyanidin chloride (69.76 ± 8.02 μg/g extract), cyanidin-3-O-glucoside (903.66 ± 101.89 μg/g extract), and punicalagin (992.09 ± 174.53 μg/g extract), was found to demonstrate the strongest cytotoxic activity on MCF-7 breast cancer cell lines by decreasing the cell viability in half at 24th hour with an IC50 value of 49.08 µg/ml. PRACTICAL APPLICATIONS: Eight commercially valuable pomegranate (Punica granatum) cultivars from Turkey were examined. Pelargonidin, cyanidin, cyanidin-3-O-gl, callistephin, and delphinidin-3-O-gl were quantified. Two cultivars (P1 and P3) showed comparatively higher antioxidant effects. A cultivar (P7) showed strongest cytotoxic activity against MCF-7 breast cancer cell line. The cultivars have potential to be used as natural antioxidant and anticancer agents.

Keywords:  LC-MS/MS; MCF-7; antioxidant; cultivated; cytotoxicity; pomegranate

DOI:  https://doi.org/10.1111/jfbc.13904
Bioinformation. 2021 ;17(1): 171-180

D-carvone induced ROS mediated apoptotic cell death in human leukemic cell lines (Molt-4).

Petchi Iyappan, M Devi Bala, M Sureshkumar, Vishnu Priya Veeraraghavan, Arulselvan Palanisamy.

  The immature lymphoid cells with chromosomal structural and numerical abnormalities cause the acute lymphoblastic leukemia (ALL). This hematologic disorder constitutes about 25% of cancer prognosis among children and adolescents. D-Carvone, a monocyclic monoterpene obtained from the essential oils extracted from plants is reported to possess the various biological activities. The present study was aimed to investigate the anticancer potential of D-Carvone against the human leukemic Molt-4 cells. The cytotoxicity of DCarvone was analyzed by MTT assay. The level of lipid peroxidation and antioxidants were determined. The intracellular ROS, MMP and apoptosis were demonstrated by fluorescent staining techniques. The MTT assay revealed that the D-Carvone treatment suppressed the viability of Molt-4 cells and the IC50 was determined at 20 µM/ml. The D-Carvone treatment was increased the oxidative stress and reduced the level of antioxidants in the Molt-4 cell lines. The increased intracellular ROS, apoptotic cell death, and diminished MMP was noted in the D-Carvone treatment. In the Molt-4 cells, D-carvone induced the apoptosis in a time and dose dependent manner by the activation of caspases-8, -9 and -3. Thus, data provide insights for the clinical application of D-Carvone in the treatment of blood cancer Molt-4 cells. Our study suggests the therapeutic potential D-Carvone for the treatment of leukemia in future.

Keywords:  D-Carvone; Human leukemic cells; MOLT-4 cells; antioxidants; apoptosis; mitochondrial membrane potential

DOI:  https://doi.org/10.6026/97320630017171