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"Hif inhibitor"

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
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
Jian Yang, Cuiying Liu, Xiangnan Du, Menglei Liu, Xunming Ji, Huishan Du, Heng Zhao
BACKGROUND: Limb remote ischemic preconditioning (RIPC) protects against brain injury induced by stroke, but the underlying protective mechanisms remain unknown. As hypoxia inducible factor 1α (HIF-1α) is neuroprotective in stroke and mediates neuroinflammation, we tested the hypothesis that HIF-1α is a key factor of RIPC against stroke by mediating inflammation. METHODS AND RESULTS: Stroke was induced by transient middle cerebral artery occlusion in rats, and RIPC was conducted in both hind limbs...
February 24, 2018: Journal of the American Heart Association
Andrea L Frump, Mona Selej, Jordan A Wood, Marjorie Albrecht, Bakhtiyor Yakubov, Irina Petrache, Tim Lahm
17β-estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible remain unknown. We hypothesized the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague Dawley rats or ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs)...
February 2, 2018: American Journal of Respiratory Cell and Molecular Biology
Debangshu Samanta, Youngrok Park, Xuhao Ni, Huili Li, Cynthia A Zahnow, Edward Gabrielson, Fan Pan, Gregg L Semenza
Triple-negative breast cancer (TNBC) is treated with cytotoxic chemotherapy and is often characterized by early relapse and metastasis. To form a secondary (recurrent and/or metastatic) tumor, a breast cancer cell must evade the innate and adaptive immune systems. CD47 enables cancer cells to evade killing by macrophages, whereas CD73 and PDL1 mediate independent mechanisms of evasion of cytotoxic T lymphocytes. Here, we report that treatment of human or murine TNBC cells with carboplatin, doxorubicin, gemcitabine, or paclitaxel induces the coordinate transcriptional induction of CD47, CD73, and PDL1 mRNA and protein expression, leading to a marked increase in the percentage of CD47+CD73+PDL1+ breast cancer cells...
January 24, 2018: Proceedings of the National Academy of Sciences of the United States of America
Olivier Bernard, Florence Jeny, Yurdagul Uzunhan, Elisabetta Dondi, Rahma Terfous, Rabab Label, Angela Sutton, Jérôme Larghero, Valérie Vanneaux, Hilario Nunes, Emilie Boncoeur, Carole Planès, Nicolas Dard
Distal lung diseases such as pulmonary fibrosis or acute lung injury are commonly associated with local alveolar hypoxia that may be deleterious through the stimulation of alveolar epithelial cell (AEC) apoptosis. In various murine models of alveolar injury, administration of allogenic human mesenchymal stem cells (hMSC) exerts an overall protective paracrine effect limiting lung inflammation and fibrosis. However, the precise mechanisms on lung cells themselves remain poorly understood. Here we investigated whether hMSC conditioned medium (hMSC-CM) would protect AECs from hypoxia-induced apoptosis and the mechanisms involved in this cytoprotective effect...
November 22, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
Moritz J Strowitzki, Alina S Ritter, Praveen Radhakrishnan, Jonathan M Harnoss, Vanessa M Opitz, Marvin Biller, Julian Wehrmann, Ulrich Keppler, Jana Scheer, Markus Wallwiener, Thomas Schmidt, Alexis Ulrich, Martin Schneider
Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5'-Hydroxymethyl-2'-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions...
October 13, 2017: Scientific Reports
Nao Iguchi, M İrfan Dönmez, Anna P Malykhina, Alonso Carrasco, Duncan T Wilcox
Posterior urethral valves are the most common cause of partial bladder outlet obstruction (PBOO) in the pediatric population. Pathological changes in the bladder developed during PBOO are responsible for long-lasting voiding dysfunction in this population despite early surgical interventions. Increasing evidence showed PBOO induces an upregulation of hypoxia-inducible factors (HIFs) and their transcriptional target genes, and they play a role in pathophysiological changes in the obstructed bladders. We hypothesized that blocking HIF pathways can prevent PBOO-induced bladder dysfunction...
November 1, 2017: American Journal of Physiology. Renal Physiology
Toshihide Kurihara
The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-type-specific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells...
June 6, 2017: Keio Journal of Medicine
Sanghyuck Lee, Oh Seok Kwon, Chang-Soo Lee, Misun Won, Hyun Seung Ban, Choon Sup Ra
We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC50 values of 0.60-0...
July 1, 2017: Bioorganic & Medicinal Chemistry Letters
Tianchi Yu, Bo Tang, Xueying Sun
Hypoxia is frequently observed in solid tumors and also one of the major obstacles for effective cancer therapies. Cancer cells take advantage of their ability to adapt hypoxia to initiate a special transcriptional program that renders them more aggressive biological behaviors. Hypoxia-inducible factors (HIFs) are the key factors that control hypoxia-inducible pathways by regulating the expression of a vast array of genes involved in cancer progression and treatment resistance. HIFs, mainly HIF-1 and -2, have become potential targets for developing novel cancer therapeutics...
May 2017: Yonsei Medical Journal
Samantha Tarshis, Joanne Maltzahn, Zoe Loomis, David C Irwin
BACKGROUND: High altitude cerebral edema (HACE) is a fulminant, deadly, and yet still unpredictable brain disease. A new prophylactic treatment for HACE and its predecessor, acute mountain sickness (AMS), needs to be developed without the contraindications or adverse effect profiles of acetazolamide and dexamethasone. Since neovascularization signals are likely key contributors to HACE/AMS, our approach was to examine already existing anti-angiogenic drugs to inhibit potential initiating HACE pathway(s)...
December 1, 2016: Aerospace Medicine and Human Performance
Haiquan Lu, Ivan Chen, Larissa A Shimoda, Youngrok Park, Chuanzhao Zhang, Linh Tran, Huimin Zhang, Gregg L Semenza
Breast cancer stem cells (BCSCs) play a critical role in tumor recurrence and metastasis. Exposure of breast cancer cells to chemotherapy leads to an enrichment of BCSCs. Here, we find that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. Knockdown of GSTO1 expression abrogates carboplatin-induced BCSC enrichment, decreases tumor initiation and metastatic capacity, and delays tumor recurrence after chemotherapy...
February 21, 2017: Cell Reports
Tomoko Mutoh, Tatsushi Mutoh, Kazuhiro Nakamura, Kazumasu Sasaki, Yasuko Tatewaki, Tatsuya Ishikawa, Yasuyuki Taki
Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2...
December 23, 2016: Brain Research Bulletin
Marie-José Lecomte, Séverine Pechberty, Cécile Machado, Sandra Da Barroca, Philippe Ravassard, Raphaël Scharfmann, Paul Czernichow, Bertrand Duvillié
Innovative treatments to cure type 1 diabetes are being actively researched. Among the different strategies, the replacement of β-cells has given promising results. Classically, islets from cadaveric donors are transplanted into diabetic patients, but recently phase I clinical trials that use stem cell-derived β-cells have been started. Such protocols require either an immunosuppressive treatment or the macroencapsulation of the β-cells. They involve cell aggregation and the exposure of the cells to hypoxia...
December 3, 2016: Cell Medicine
Kyunghye Park, Hye Eun Lee, Sun Hee Lee, Doohyun Lee, Taeho Lee, You Mie Lee
Hypoxia occurs in a variety of pathological events, including the formation of solid tumors. Hypoxia-inducible factor (HIF)-1α is stabilized under hypoxic conditions and is a key molecule in tumor growth and angiogenesis. Seeking to develop novel cancer therapeutics, we investigated small molecules from our in-house chemical libraries to target HIF-1α. We employed a dual-luciferase assay that uses a luciferase (Luc) reporter vector harboring five copies of hypoxia-responsive element (HRE) in the promoter...
January 31, 2017: Oncotarget
Jeroen Dekervel, Ashenafi Bulle, Petra Windmolders, Diether Lambrechts, Eric Van Cutsem, Chris Verslype, Jos van Pelt
Epithelial-to-mesenchymal transition (EMT) is linked to tumor invasion, drug resistance and aggressive disease and this is largely dependent on the cell's microenvironment. Acriflavine (ACF) is an old antibacterial drug recently also suggested as anticancer agent and HIF inhibitor. We wanted to study the effect of acriflavine on EMT in different human cancer models. Pancreatic cancer cells (Panc-1) were exposed to TGF-β1 or cobalt chloride (to mimick severe hypoxia) to induce EMT. For our third model we exposed HepG2 liver cancer cells to sorafenib which resulted in development of acquired drug resistance with strong features of EMT and aggressive behavior...
February 2017: Translational Oncology
Takahiro Isono, Tokuhiro Chano, Tetsuya Yoshida, Susumu Kageyama, Akihiro Kawauchi, Masafumi Suzaki, Takeshi Yuasa
Dormant cancer cells are deprivation-resistant, and cause a number of problems for therapeutic approaches for cancers. Renal cell carcinomas (RCCs) include deprivation-resistant cells that are resistant to various treatments. In this study, the specific characteristics of deprivation-resistant cells were transcriptionally identified by next generation sequencing. The hypoxia-inducible factors (HIF) transcription factor network was significantly enhanced in deprivation-resistant RCCs compared to the sensitive RCCs...
2016: American Journal of Cancer Research
Xiaofan Guo, Hao Xue, Qianqian Shao, Jian Wang, Xing Guo, Xi Chen, Jinsen Zhang, Shugang Xu, Tong Li, Ping Zhang, Xiao Gao, Wei Qiu, Qinglin Liu, Gang Li
Tumor-associated macrophages (TAMs) are enriched in gliomas and help create a tumor-immunosuppressive microenvironment. A distinct M2-skewed type of macrophages makes up the majority of glioma TAMs, and these cells exhibit pro-tumor functions. Gliomas contain large hypoxic areas, and the presence of a correlation between the density of M2-polarized TAMs and hypoxic areas suggests that hypoxia plays a supportive role during TAM recruitment and induction. Here, we investigated the effects of hypoxia on human macrophage recruitment and M2 polarization...
December 6, 2016: Oncotarget
Yasuyuki Ikezawa, Jun Sakakibara-Konishi, Hidenori Mizugaki, Satoshi Oizumi, Masaharu Nishimura
BACKGROUND: The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor γ secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation...
February 2017: International Journal of Clinical Oncology
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