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hypoxia tumor

Dinghua Liang, Xing Wu, Brian B Hasinoff, David E Herbert, Geoffrey K Tranmer
As part of our initial efforts into developing a tumor-targeting therapy, C-10 substituted derivatives of a camptothecin analog (SN-38) have been synthesized (2-, 3- and 4-nitrobenzyl) for use as potential hypoxia-activated prodrugs and evaluated for their cytotoxicity, topoisomerase I inhibition and electrochemical (reductive) properties. All three derivatives were found to possess reduced toxicity towards human leukemia K562 cells compared to SN-38, validating a condition for prodrug action. Using an MTS assay, IC50 's were found to be 3...
August 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jonas Steenbrugge, Koen Breyne, Kristel Demeyere, Olivier De Wever, Niek N Sanders, Wim Van Den Broeck, Cecile Colpaert, Peter Vermeulen, Steven Van Laere, Evelyne Meyer
BACKGROUND: Murine breast cancer models relying on intraductal tumor cell inoculations are attractive because they allow the study of breast cancer from early ductal carcinoma in situ to metastasis. Using a fully immunocompetent 4T1-based intraductal model for triple-negative breast cancer (TNBC) we aimed to investigate the immunological responses that guide such intraductal tumor progression, focusing on the prominent role of macrophages. METHODS: Intraductal inoculations were performed in lactating female mice with luciferase-expressing 4T1 mammary tumor cells either with or without additional RAW264...
August 15, 2018: Journal of Experimental & Clinical Cancer Research: CR
Myung-Chul Kim, Sung-Hyun Hwang, Na-Yon Kim, Hong-Seok Lee, Sumin Ji, Yeseul Yang, Yongbaek Kim
BACKGROUND: Hypoxia is a hallmark of the solid tumor microenvironment and is associated with poor outcomes in cancer patients. The present study was performed to investigate mechanisms underlying the hypoxia-induced phenotypic changes using human malignant mesothelioma (HMM) cells. METHODS: Hypoxic conditions were achieved by incubating HMM cells in the air chamber. The effect of hypoxia on phenotype changes in HMM cells was investigated by performing in vitro clonogenicity, drug resistance, migration, and invasion assays...
August 15, 2018: BMC Cancer
Okyaz Eminaga, Jochen Fries, Susanne Neiß, Michaela Heitmann, Fabian Wötzel, Axel Heidenreich, Christiane Bruns, Hakan Alakus, Ute Warnecke-Eberz
AIM: To show the association between the expression level of hsa-miR-210 (miR-210) and tumor progression in prostate cancer (PCa). METHODS: Quantitative PCR was performed to measure miR-210 on 55 subjects with different tumor stages; our results were then validated using three external datasets. ANOVA and Tukey's post hoc analysis were performed for comparative analyses between different tumor stages. Using the transcriptome data from The Cancer Genome Atlas for CaP, the gene expression analyses were performed on experimentally validated target genes of miR-210 identified in Tarbase and miRWalk datasets...
August 15, 2018: Epigenomics
Rodrigo Toledo, Camilo Jimenez
Inactivating mutations of the succinate dehydrogenase subunit B ( SDHB ) gene and the subsequent stabilization and activation of the hypoxia-inducible factor 2-alpha (HIF2α) unit are recognized hallmarks associated with the development of metastatic pheochromocytomas and paragangliomas (MPPG). Despite this discovery, the development of systemic therapies for patients with MPPG has been very slow. The rarity of the disease, the lack of preclinical animal models, and the impracticable development of large clinical trials has hindered the therapeutic progress for MPPG...
2018: F1000Research
Qing Ruan, Xuran Zhang, Xiao Lin, Xiaojiang Duan, Junbo Zhang
Radiolabelled 2-nitroimidazoles have been used for imaging hypoxia. With the aim of developing novel 99m Tc radiotracers for imaging hypoxia, four novel 2-nitroimidazole isocyanide derivatives ( 2a , 2b , 2c , and 2d ) were synthesized and radiolabelling was carried out for preparing their corresponding 99m Tc complexes. These 99m Tc complexes were stable in vitro and could exhibit good hypoxic selectivity. The partition coefficient results indicated that they were hydrophilic, and an evaluation of biodistribution in mice bearing S180 tumors indicated that all of the complexes could accumulate in the tumors...
June 1, 2018: MedChemComm
Sitai Liang, Edward A Medina, Boajie Li, Samy L Habib
Loss of Von Hippel-Lindau (VHL) in renal carcinoma cells results in up regulation of the activity of Hypoxia-Inducible Factor (HIF-α), a major transcription factor involved in kidney cancer. Rapamycin as mTOR inhibitor and 5-aminoimidazole-4-carboxamide (AICA)-riboside (AICAR) as AMPK activator are separately used to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF-2α expression in RCC cells, including primary cells isolated from kidney cancer patients...
August 14, 2018: Molecular Oncology
Olga Astapova, Anindita Biswas, Alessandra DiMauro, Jacob Moalem, Stephen R Hammes
Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is characterized by metachronously occurring tumors including pheochromocytoma, renal cell carcinoma (RCC), and hemangioblastoma. Although VHL disease leads to reduced life expectancy, its diagnosis is often missed and tumor screening guidelines are sparse. VHL protein acts as a tumor suppressor by targeting hypoxia-inducible factors (HIFs) for degradation through an oxygen-dependent mechanism. VHL mutants with more severely reduced HIF degrading function carry a high risk of RCC, while mutants with preserved HIF degrading capacity do not cause RCC but still lead to other tumors...
2018: Case Reports in Endocrinology
Dongmei Ding, Manhui Zhu, Xiaojuan Liu, Li Jiang, Jiaowen Xu, Lili Chen, Juan Liang, Lele Li, Taohu Zhou, Ying Wang, Hao Shi, You Yuan, E Song
Choroidal neovascularization (CNV) is a type of wet age-related macular degeneration (AMD) which is a major cause of blindness in elder patients. Tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes tumor angiogenesis via upregulating the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). Additionally, TRAF6 facilitates the inflammatory response in macrophages and microglia. Here, using mouse laser-induced CNV model and TRAF6 siRNA, the study shows that TRAF6 is a critical player in CNV...
August 6, 2018: Biochemical and Biophysical Research Communications
Yue Xing, Chunliu Mi, Zhe Wang, Zhi Hong Zhang, Ming Yue Li, Hong Xiang Zuo, Jing Ying Wang, Xuejun Jin, Juan Ma
Dictamnus dasycarpus is a traditional Chinese medicine that has been commonly used in the treatment of cancer. Fraxinellone is a natural product isolated from the D. dasycarpus plant, which has been shown to exhibit neuroprotective and anti-inflammatory activities. However, whether fraxinellone exerts anticancer effects and the mechanisms by which it may inhibit tumor growth remain unknown. Here, we found that fraxinellone, in a dose-dependented manner, inhibited the expression of programmed cell death ligand-1 (PD-L1), which plays a pivotal role in tumorigenesis...
August 10, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Lingtong Meng, Yali Cheng, Xiaoning Tong, Shaoju Gan, Yawen Ding, Yu Zhang, Chao Wang, Lei Xu, Yishen Zhu, Jinhui Wu, Yiqiao Hu, Ahu Yuan
Hypoxia, and hypoxia-inducible factor-1 (HIF-1), can induce tumor resistance to radiation therapy. To overcome hypoxia-induced radiation resistance, recent studies have described nano-systems to improve tumor oxygenation for immobilizing DNA damage and simultaneously initiate oxygen-dependent HIF-1α degradation. However, HIF-1α degradation is incomplete during tumor oxygenation treatment alone. Therefore, tumor oxygenation combined with residual HIF-1 functional inhibition is crucial to optimizing therapeutic outcomes of radiotherapy...
August 13, 2018: ACS Nano
Olivia J Kelada, Roy H Decker, Sameer K Nath, Kimberly L Johung, Ming-Qiang Zheng, Yiyun Huang, Jean-Dominique Gallezot, Chi Liu, Richard E Carson, Uwe Oelfke, David J Carlson
PURPOSE: Tumor hypoxia correlates with treatment failure in patients undergoing conventional radiation therapy. However, no published studies have investigated tumor hypoxia in patients undergoing stereotactic body radiation therapy (SBRT). We aimed to noninvasively quantify the tumor hypoxic volume (HV) in non-small cell lung cancer (NSCLC) tumors to elucidate the potential role of tumor vascular response and reoxygenation at high single doses. METHODS AND MATERIALS: Six SBRT-eligible patients with NSCLC tumors >1 cm were prospectively enrolled in an institutional review board-approved study...
September 1, 2018: International Journal of Radiation Oncology, Biology, Physics
Yanjing Li, Hong Sui, Cailing Jiang, Shumin Li, Yu Han, Peng Huang, Xiaoxue Du, Jingwen Du, Yuxian Bai
BACKGROUND/AIMS: Although photodynamic therapy (PDT) can relieve esophageal obstruction and prolong survival time of patients with esophageal cancer, it can induce nuclear factor-kappa B (NF-κB) activation in many cancers, which plays a negative role in PDT. Dihydroartemisinin (DHA), the most potent artemisinin derivative, can enhance the effect of PDT on esophageal cancer cells. However, the mechanism is still unclear. METHODS: We generated stable cell lines expressing the super-repressor form of the NF-κB inhibitor IκBα and cell lines with lentivirus vector-mediated silencing of the HIF-1α gene...
August 10, 2018: Cellular Physiology and Biochemistry
Hui Zhang, Qing Ye, Zhenfang Du, Min Huang, Ming Zhang, Huifeng Tan
MicroRNAs (miRNAs) have been implicated in a large number of biological processes such as tumor angiogenesis. MiR-148b-3p has been identified as a tumor suppressor in multiple cancer types and the function of miR-148b-3p in renal carcinoma remains unidentified. In this study, we found that the expression of miR-148b-3p was decreased in renal carcinoma based on GEO analysis and the gain-of-function experiments revealed that miR-148b-3p promoted renal carcinoma cell apoptosis and suppressed cell proliferation, migration in vitro and tumor growth in vivo...
August 9, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Chuchu Shao, Fengming Yang, Suyu Miao, Weitao Liu, Chaoshan Wang, Yongqian Shu, Hua Shen
PURPOSE: Hypoxia is a major regulator of angiogenesis and always influences the release of exosomes in various types of tumors. The present review aimed to assess the role of hypoxia-induced exosomes in the tumor biology. METHODS: The relevant publications were retrieved from PubMed using keywords such as hypoxia, exosome, extracellular vesicles, tumor, cancer, and other similar terms. RESULTS: Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions...
August 11, 2018: Molecular Cancer
Wei Yin, Ming Qiang, Wendong Ke, Yu Han, Jean Felix Mukerabigwi, Zhishen Ge
Radiosensitizers play an important role in the clinical radiotherapy of hypoxic solid tumors to improve therapeutic efficacy. However, the in vivo performance of clinically used small-molecule radiosensitizers is commonly compromised by low bioavailability in hypoxic tumor regions. Herein, amphiphilic block copolymer radiosensitizers are prepared from clinically approved poly(ethylene glycol)-block-poly(l-glutamic acid) (PEG-b-PLG) and metronidazole (MN) to obtain MN-grafted PEG-b-PLG (PEG-b-P(LG-g-MN)) via condensation reaction, which can self-assemble into core-shell micelles as nanoparticle-formulated radiosensitizers in aqueous solution...
August 4, 2018: Biomaterials
Xin Chen, Jieru Zhou, Xiaoduan Li, Xinjing Wang, Yingying Lin, Xipeng Wang
Recently, cancer has been considered to be a complex system that includes the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most common immune-related stromal cells in the TME, and communication between cancer cells and TAMs is crucial for the progression of epithelial ovarian cancer (EOC). In this study, we revealed that exosomes derived from EOC cells remodel macrophages to a tumor-promoted phenotype, namely TAMs. In addition, hypoxic microenvironments have been postulated to facilitate this process in the TME, and hypoxia-inducible factors (HIFs) play an important role in this process...
August 8, 2018: Cancer Letters
Anne Riemann, Sarah Reime, Oliver Thews
Hypoxia can control the expression of miRNAs in tumors which play an important role for the control of the malignant behavior. The aim of the study was to analyze whether extracellular acidosis, a common feature of tumors, also has an impact on the miRNA expression in isolated cells as well as in solid tumors. MiRNA expression was analyzed in two rat tumor cell lines (AT1 prostate and Walker-256 mammary carcinomas) by NGS and qPCR. In vivo the same cell lines were implanted subcutaneously and the tumor pH was modulated by inspiratory hypoxia and inhibition of the respiratory chain...
August 11, 2018: International Journal of Cancer. Journal International du Cancer
Hairong Wang, Yu Chao, Jingjing Liu, Wenwen Zhu, Guanglin Wang, Ligeng Xu, Zhuang Liu
Tumor hypoxia is known to be one of critical factors that aggravate the tumor resistance to photodynamic therapy (PDT) in which oxygen is essential for tumor destruction. Herein, catalase, an enzyme to trigger hydrogen peroxide (H2 O2 ) decomposition, is modified by in-situ free radical polymerization, using meso-tetra(p-hydroxyphenyl) porphine (THPP) as the cross-linker to enable condensed grafting of short polyethylene glycol (PEG) chains on the protein surface as a permeable brush-like safeguard. The formulated catalase-entrapped nanocapsules (CAT-THPP-PEG) with enhanced enzyme stability can be labeled with 99m Tc4+ , a radioisotope ion that is chelated by the porphyrin structure of THPP, to allow in vivo single-photon emission computed tomography (SPECT) imaging...
August 4, 2018: Biomaterials
Lihua Zhou, Yayun Wu, Xiaoqing Meng, Sanpeng Li, Jiali Zhang, Ping Gong, Pengfei Zhang, Tao Jiang, Guanjun Deng, Wenjun Li, Zhihong Sun, Lintao Cai
Phototherapy is a promising treatment method for cancer therapy. However, the various factors have greatly restricted phototherapy development, including the poor accumulation of photosensitizer in tumor, hypoxia in solid tumor tissue and systemic phototoxicity. Herein, a mitochondrial-targeted multifunctional dye-anchored manganese oxide nanoparticle (IR808@MnO NP) is developed for enhancing phototherapy of cancer. In this nanoplatform, IR808 as a small molecule dye acts as a tumor targeting ligand to make IR808@MnO NPs with capacity to actively target tumor cells and relocate finally in the mitochondria...
August 10, 2018: Small
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