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Hif inhibitor

Hadas Pahima, Simona Reina, Noa Tadmor, Daniella Dadon-Klein, Anna Shteinfer-Kuzmine, Nathalie M Mazure, Vito De Pinto, Varda Shoshan-Barmatz
The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane (OMM) protein, serves as a mitochondrial gatekeeper, mediating the transport of nucleotides, Ca2+ and other metabolites across the OMM. VDAC1 also plays a central role in mitochondria-mediated apoptosis by facilitating the release of apoptotic proteins and by association with both pro- and anti-apoptotic proteins. Tumor cells, which are constantly exposed to hypoxic conditions, affect the cell via the transcription factor hypoxia-inducible factor (HIF) that induces transcriptional activity...
February 27, 2018: Oncotarget
Regina Trollmann, Theresa Mühlberger, Mandy Richter, Gudrun Boie, Andreas Feigenspan, Florian Brackmann, Susan Jung
Angiogenesis due to hypoxic-ischemic (HI) injury represents a crucial compensatory mechanism of the developing brain that is mainly regulated by hypoxia-inducible transcription factors (HIF). Pharmacological stimulation of HIF is suggested as a neuroprotective option, however, studies of its effects on vascular development are limited. We analyzed the influence of the prolyl-4-hydroxylase inhibitor (PHI), FG-4497, and erythropoietin (rhEPO) on post-hypoxic angiogenesis (angiogenic growth factors, vessel structures) in the developing mouse brain (P7) assessed after a regeneration period of 72 h...
March 13, 2018: Brain Research
Kinga A Kocemba-Pilarczyk, Barbara Ostrowska, Sonia Trojan, Ecce Aslan, Dorota Kusior, Małgorzata Lasota, Claire Lenouvel, Joanna Dulińska-Litewka
Multiple myeloma (MM) is characterized as a clonal expansion of malignant plasma cells in the bone marrow, which is often associated with pancytopenia and osteolytic bone disease. Interestingly, myeloma-infiltrated bone marrow is considered to be hypoxic, providing selection pressure for a developing tumour. Since HSP90 was shown to participate in stabilization of the subunit of the key transcription factor HIF-1, which controls the hypoxic response, the aim of this study was to investigate the influence of a HSP90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG), on MM cells cultured under low oxygenation conditions...
March 15, 2018: Acta Biochimica Polonica
Yongchang Lai, Zhijian Zhao, Tao Zeng, Xiongfa Liang, Dong Chen, Xiaolu Duan, Guohua Zeng, Wenqi Wu
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy...
2018: Cancer Cell International
Xiaomeng Dai, Guoliang Pi, Sheng-Li Yang, George G Chen, Li-Ping Liu, Han-Hua Dong
OBJECTIVE: To investigate the correlation between the expression of PD-L1 and HIF-1α in hepatocellular carcinoma (HCC) tissue and further analyze the association with clinical parameters and the prognostic value of coexpression in HCC patients. METHODS: We assessed the expression of PD-L1 and HIF-1α by immunohistochemistry in tumor tissue from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients...
March 8, 2018: Translational Oncology
Jinfeng Qu, Lei Zhang, Lanyu Li, Yujie Su
This study was aimed to investigate the tumor suppressive role of miR-148b in regulating endoplasmic reticulum metalloprotease 1 (ERMP1) expression and oxidative stress response in endometrial cancer cells. Human endometrial cancer RL95-2 cells were used and transfected with miR-148b mimic, miR-148b inhibitor, and their scrambled negative control. Thereafter, the transfection efficiency was determined by qRT-PCR and cell viability was assessed by MTT assay. The luciferase reporter assay, Western blot, and qRT-PCR were conducted to determine the target gene of miR-148b...
March 9, 2018: Oncology Research
Ru Zhao Dong, Feng Xiao Dong, Qi Tianq Liu, Ting Xu Zhi, Jie Zou, Tao Jing Zhong, Tao Li, Lan Xiang Mo, Wei Zhou, Wen Wen Guo, Xia Liu, Yuan Yuan Chen, Yang Meng Li, Xiao Gang Zhong, Min Ya Han, Hao Zhong Wang
PURPOSE: Hypoxia-inducible factor (HIF)-2α is regarded as a preferential target for individualized HCC treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF-2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF-2α activity and of sorafenib resistance in hypoxic HCC cells. EXPERIMENTAL DESIGN: The cell viability, migration and invasion abilities were measured to analyze the effects of HIF-2α on hypoxic HCC cells...
March 7, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Maya Barben, Christian Schori, Marijana Samardzija, Christian Grimm
BACKGROUND: Degeneration of cone photoreceptors leads to loss of vision in patients suffering from age-related macular degeneration (AMD) and other cone dystrophies. Evidence, such as choroidal ischemia and decreased choroidal blood flow, implicates reduced tissue oxygenation in AMD pathology and suggests a role of the cellular response to hypoxia in disease onset and progression. Such a chronic hypoxic situation may promote several cellular responses including stabilization of hypoxia-inducible factors (HIFs)...
March 7, 2018: Molecular Neurodegeneration
Theodoros Eleftheriadis, Georgios Pissas, Vassilios Liakopoulos, Ioannis Stefanidis
Indoleamine 2, 3-dioxygenase (IDO) suppresses T-cell function at least in part by altering cell metabolism. Hypoxia-inducible factor-1 (HIF-1) increases upon T-cell activation and alters cell metabolism favoring their differentiation to effector cells. The effect of IDO on HIF-1α expression and activity was evaluated. For this purpose, mixed lymphocyte reaction (MLR) was performed using the IDO inhibitor 1-DL-methyl-tryptophan and the p53 inhibitor pifithrin-α. L-tryptophan degradation and cell proliferation were assessed by enzyme-linked immunosorbent assay, whereas the expression of proteins of interest by western blotting...
February 2018: Iranian Journal of Allergy, Asthma, and Immunology
M K Iqbal, F Nabi, M U Rehman, K Mehmood, S Huang, H Zhang, L Zhang, M Iqbal, J Li
Tibial dyschondroplasia (TD) is a disease of many avian species characterized by an enlarged and avascular lesion in the proximal tibiotarsal bone. The aim of present study was to evaluate the effects of hypoxia-inducible factor-1α(HIF-1α) inhibition on thiram- induced TD using synthetic medicine FK228 and the association between HIF-1α and heat-shock protein 90 (Hsp90). One hundred and fifty broiler chicks were equally divided into 3 groups: control; thiram fed; and FK228 treatment. Expressions of HIF-1α and Hsp90 genes were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR) on day 10 and 14 post-hatch...
January 2018: Journal of Biological Regulators and Homeostatic Agents
Yaling Yu, Haomin Cui, Chuan Chen, Gen Wen, Jia Xu, Binbin Zheng, Jianse Zhang, Chunyang Wang, Yimin Chai, Jin Mei
Although mammalian kidney regeneration has been reported to occur throughout life, mature kidneys in mammals are not thought to regenerate sufficiently, particularly glomeruli. In our previous work, we found that renal regeneration could be enhanced by decellularized renal scaffolds after partial nephrectomy. In this study, we verified that the enhanced renal regeneration mediated by decellularized scaffolds could be attributed to regenerated glomeruli, which were counted both indirectly and directly under a microscope...
February 24, 2018: Biomaterials
Ezinne Ozurumba, Omana Mathew, Katsuri Ranganna, Myung Choi, Adebayo Oyekan
BACKGROUND: Hypoxia inducible factor (HIF)/prolyl hydroxylase domain (PHD)-containing proteins are involved in renal adaptive response to high salt (HS). Peroxisome proliferator activated receptor alpha (PPARα), a transcription factor involved in fatty acid oxidation is implicated in the regulation of renal function. As both HIF-1α/PHD and PPARα contribute to the adaptive changes to altered oxygen tension, this study tested the hypothesis that PHD-induced renal adaptive response to HS is PPARα-dependent...
March 28, 2018: Journal of Basic and Clinical Physiology and Pharmacology
Haet Nim Lim, Jun-Pil Jang, Jang Mi Han, Jae-Hyuk Jang, Jong Seog Ahn, Hye Jin Jung
Angiogenesis plays a very important role in tumor progression through the creation of new blood vessels. Therefore, angiogenesis inhibitors could contribute to cancer treatment. Here, we show that a microbial metabolite, elaiophylin, exhibits potent antiangiogenic activity from in vitro and in vivo angiogenesis assays. Elaiophylin dramatically suppressed in vitro angiogenic characteristics such as proliferation, migration, adhesion, invasion and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by vascular endothelial growth factor (VEGF) at non-toxic concentrations...
March 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Yukino Kobayashi, Ami Oguro, Susumu Imaoka
Bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl)propane), one of the phenolic compounds widely used in the manufacture of plastic and epoxy resins, is known as an endocrine disruptor. In a previous study, we found that BPA induced hypoxia inducible factor-1alpha (HIF-1alpha) degradation by dissociation from heat shock protein 90 (Hsp90). In this study, to investigate the structural requirements for degradation of HIF-1alpha, we estimated the effect of BPA derivatives (BPE, BPF, BPB, Dimethyl butylidene diphenol (DMBDP), Ethyl hexylidene diphenol (EHDP), Bishydroxyphenyl cyclohexane (BHCH), and Methyl benzylidene bisphenol (MBBP)) on HIF-1alpha protein degradation, using human hepatocarcinoma cell line, Hep3B...
2018: Biological & Pharmaceutical Bulletin
Saki Kaneko, Chiaki Sato, Nobuya Shiozawa, Ayami Sato, Hiromi Sato, Nantiga Virgona, Tomohiro Yano
BACKGROUND/AIM: A hallmark of the progression of prostate cancer to advanced disease is the acquisition of androgen-independent growth. This malignant phenotype is characterized by resistance to conventional treatments and predisposes to formation of hypoxic regions containing stem-like cancer cells. Unfortunately, an effective therapy to target prostate cancer stem cells under hypoxia has not yet been established. In this report, we studied whether δ-tocotrienol (T3), a vitamin E family member that has exhibited the most potent anti-cancer activity, could suppress the survival of prostate cancer stem-like cells...
March 2018: Anticancer Research
Stefano Motta, Claudia Minici, Dario Corrada, Laura Bonati, Alessandro Pandini
Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-α degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-α transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF-α:ARNT dimerization has been proposed as a promising therapeutic strategy...
February 28, 2018: PLoS Computational Biology
Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Yan Song, Paul Richardson, Noopur Raje, Nikhil C Munshi, Kenneth C Anderson
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+ CD25+ FoxP3+ regulatory T cells, and HLA-DRLow/- CD11b+ CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients...
February 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Hartmut Beck, Mario Jeske, Kai Thede, Friederike Stoll, Ingo Flamme, Metin Akbaba, Jens-Kerim Ergüden, Gunter Karig, Jörg Keldenich, Felix Oehme, Hans-Christian Militzer, Ingo V Hartung, Uwe Thuss
Small molecule inhibitors of hypoxia inducible factor prolyl hydroxylases (HIF-PHs) are currently under clinical development as novel treatment option for chronic kidney disease (CKD) associated anemia. Inhibition of HIF-PH mimics hypoxia and leads to increased EPO expression and subsequently increased erythropoiesis. Herein we describe the discovery, synthesis, SAR and proposed binding mode of novel 2,4-diheteroaryl-1,2-dihydro-3H-pyrazol-3-ones as orally bioavailable HIF-PH inhibitors for the treatment of anemia...
February 27, 2018: ChemMedChem
Ruimeng Yang, Chong Duan, Liya Yuan, John A Engelbach, Christina I Tsien, Scott C Beeman, Carlos J Perez-Torres, Xia Ge, Keith M Rich, Joseph J H Ackerman, Joel R Garbow
PURPOSE: There is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia-inducible factor 1α (HIF-1α)-CXC chemokine receptor 4 (CXCR4) pathway may contribute to the pathogenesis of late-onset, irradiation-induced necrosis. This study investigates the mitigative efficacy of an HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis (RN) in an intracranial mouse model. METHODS AND MATERIALS: Mice received a single-fraction, 50-Gy dose of hemispheric irradiation from the Leksell Gamma Knife Perfexion and were then treated with either topotecan, an HIF-1α inhibitor, from 1 to 12 weeks after irradiation, or AMD3100, a CXCR4 antagonist, from 4 to 12 weeks after irradiation...
March 15, 2018: International Journal of Radiation Oncology, Biology, Physics
Mohit Sharma, Smitha Sammith Shetty, Raghu Radhakrishnan
BACKGROUND: Oral submucous fibrosis is an oral potentially malignant disorder with high incidence of malignant transformation and rising global prevalence. However, the genesis of oral submucous fibrosis is still unclear despite superfluity of literature. In the background of ineffective treatment, it is necessary to decode its onset and progression before designing customized treatment regimens. OBJECTIVE: The objective of this article is to decipher the pathogenesis of oral submucous fibrosis in order to identify novel drug targets...
February 26, 2018: Recent Patents on Anti-cancer Drug Discovery
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