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"Hif inhibitor"

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...
September 2, 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...
August 23, 2016: International Journal of Clinical Oncology
David Kung-Chun Chiu, Iris Ming-Jing Xu, Robin Kit-Ho Lai, Aki Pui-Wah Tse, Larry Lai Wei, Hui-Yu Koh, Lynna Lan Li, Derek Lee, Regina Cheuk-Lam Lo, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong
UNLABELLED: A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment...
September 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Saima Subhani, Divya Teja Vavilala, Mridul Mukherji
Aberrant activation of the hypoxia inducible factor (HIF) pathway causing overexpression of angiogenic genes, like vascular endothelial growth factor (VEGF), is one of the underlying causes of ocular neovascularization (NV) and metastatic cancer. Consistently, along with surgical interventions, a number of anti-VEGF agents have been approved by FDA for the treatment of ocular neovascular diseases. These anti-VEGF agents, like ranibizumab/lucentis, have revolutionized the treatment in the past decade. However, substantial vision improvement is observed only in a subset of age-related macular degeneration patients receiving ranibizumab...
July 2016: Angiogenesis
Tomoko Mutoh, Tatsushi Mutoh, Kazumasu Sasaki, Yukiko Yamamoto, Yoshiharu Tsuru, Hirokazu Tsubone, Tatsuya Ishikawa, Yasuyuki Taki
AIMS: Neurocardiac dysfunction is a life-threatening systemic consequence of subarachnoid hemorrhage (SAH) that contributes to triggering delayed cerebral ischemia (DCI). This study aimed to determine the impact of dobutamine cardiac support during isoflurane postconditioning on post-SAH DCI. MAIN METHODS: Male C57BL/6 mice were subjected to SAH, SAH plus isoflurane postconditioning, or SAH plus isoflurane postconditioning with dobutamine. Severity of SAH was graded from 1 to 4 (mild, 1-2; severe, 3-4) based on T2*-weighted magnetic resonance imaging (MRI)...
May 15, 2016: Life Sciences
Fuquan Zhang, Shanzhou Duan, Ying Tsai, Peter C Keng, Yongbing Chen, Soo Ok Lee, Yuhchyau Chen
Cisplatin-resistant A549 and H157 (A549CisR and H157CisR) non-small cell lung cancer cells show increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether interleukin-6 (IL-6) signaling contributes to this increased stemness in cisplatin-resistant cells. When A549CisR and H157CisR cells were treated with neutralizing IL-6 antibody, decreased cisplatin resistance was observed, whereas IL-6 treatment of parental cells resulted in increased cisplatin resistance. Expression of the CSC markers was significantly upregulated in IL-6-expressing scramble cells (in vitro) and scramble cell-derived tumor tissues (in vivo) after cisplatin treatment, but not in IL-6 knocked down (IL-6si) (in vitro) cells and in IL-6si cell-derived tumor tissues (in vivo), suggesting the importance of IL-6 signaling in triggering increased stemness during cisplatin resistance development...
June 2016: Cancer Science
Hyun Seung Ban, Yoshikazu Uto, Misun Won, Hiroyuki Nakamura
INTRODUCTION: Hypoxia-inducible factor (HIF)-1α regulates the expression of genes involved in angiogenesis, cellular energy metabolism, and cell survival during cancer development. The increased expression of HIF-1α in most solid tumors is associated with poor prognoses and therapeutic outcomes. Therefore, HIF has been recognized as an attractive target for cancer therapy, and many HIF inhibitors have been reported. AREAS COVERED: This patent survey summarizes the information about patented HIF inhibitors over the last 5 years (2011-2015)...
2016: Expert Opinion on Therapeutic Patents
Robin Kit-Ho Lai, Iris Ming-Jing Xu, David Kung-Chun Chiu, Aki Pui-Wah Tse, Larry Lai Wei, Cheuk-Ting Law, Derek Lee, Chun-Ming Wong, Maria Pik Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong
PURPOSE: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. EXPERIMENTAL DESIGN: Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing...
June 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kevin Rouault-Pierre, Ashley Hamilton, Dominique Bonnet
INTRODUCTION: Hypoxia inducible factors (HIF-1α and HIF-2α) are the main mediators of hypoxic responses that operate in both normal and pathological conditions. Recent evidence indicates that HIF-1α and HIF-2α could have overlapping, unique and even sometimes opposing activities in both normal physiology and disease. Despite an increase in our understanding of the different pathways regulated by HIF-1α and HIF-2α, the role played by each factor in HSC maintenance and leukemogenesis is still controversial...
2016: Expert Opinion on Biological Therapy
Gregg L Semenza
Stem cells are characterized by the capacity for both self-renewal and generation of all other cell types (pluripotency) or differentiated cells within a particular lineage (multipotency). Stem cells are often localized to hypoxic niches within tissues and hypoxia inducible factors (HIFs) play key roles in the maintenance of pluripotent and multipotent stem cells, as well as cancer stem cells, which are also known as tumor-initiating cells. HIF inhibitors target cancer stem cells and improve the responses to angiogenesis inhibitors and cytotoxic chemotherapy in mouse models of breast cancer...
February 2016: Molecular Aspects of Medicine
Gregg L Semenza
The small subpopulation of breast cancer cells that possess the capability for self-renewal and formation of secondary tumours that recapitulate the heterogeneity of the primary tumour are referred to as tumour-initiating cells or BCSCs (breast cancer stem cells). The hypoxic tumour microenvironment and chemotherapy actively induce the BCSC phenotype. HIFs (hypoxia-inducible factors) are required and molecular mechanisms by which they promote the BCSC phenotype have recently been delineated. HIF inhibitors block chemotherapy-induced enrichment of BCSCs, suggesting that their use may improve the response to chemotherapy and increase the survival of breast cancer patients...
December 2015: Clinical Science (1979-)
Ravi Naik, Seunghyeon Han, Kyeong Lee
Intratumoral hypoxia has long been considered to be a driving force in tumor progression as well as a negative prognostic factor in human cancers. The discovery of hypoxia inducible factors (HIFs), which mediate transcriptional responses to changes in oxygen levels, has renewed enthusiasm for drug discovery and the development of targeted therapies in this field. LW6 represents an important new class of small molecules that inhibit HIF-1; it has been major source for diverse lead compounds including HIF-1α inhibitors...
September 2015: Archives of Pharmacal Research
Wenbin Song, Chiuan-Ren Yeh, Dalin He, Yong Wang, Hongjun Xie, See-Tong Pang, Luke Sien-Shih Chang, Lei Li, Shuyuan Yeh
Neutrophils make up a significant portion of the infiltrated immune cells found in the tumor microenvironment. Here we found more infiltrated neutrophils in human renal cell carcinoma (RCC) lesions than adjacent benign areas. In vitro RCC studies showed that neutrophils (HL-60N cells) infiltrated toward RCC cells and subsequently enhanced RCC cell migration and invasion. Co-culture of RCC cells with HL-60N cells up-regulated ERβ, VEGFa and HIF2α mRNA levels. ERβ signals increased RCC cell migration via induction of the VEGFa/HIF2α pathway...
August 7, 2015: Oncotarget
Debangshu Samanta, Daniele M Gilkes, Pallavi Chaturvedi, Lisha Xiang, Gregg L Semenza
Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor-initiating properties and resistance to chemotherapy...
December 16, 2014: Proceedings of the National Academy of Sciences of the United States of America
Weranja K B Ranasinghe, Graham S Baldwin, Damien Bolton, Arthur Shulkes, Joseph Ischia, Oneel Patel
PURPOSE: HIF1α over expression correlates with poor prognosis in a number of cancers. Although it is widely accepted that hypoxia induces HIF1α expression up-regulation by a reduction in oxygen dependent degradation, HIF1α up-regulation under normoxic conditions is noted with increasing frequency in many cancers. We reviewed the current knowledge of mechanisms of normoxic and hypoxic HIF1α up-regulation, and its therapeutic implications with a particular focus on its role as a potential biomarker in prostate cancer...
March 2015: Journal of Urology
Fei Niu, Yan Li, Fang-Fang Lai, Xiao-Guang Chen
Hypoxia occurs in chronic and acute vascular diseases and tumor formation. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducible factor 1 (HIF-1). Tumor hypoxia mediated by HIF-1 would facilitate the likelihood of resistance to chemotherapy and radiotherapy, proliferation, metastasis and the invasive potential; all of which culminate in a decrease in patient survival. And HIF-1 alpha subunit decides the activity of HIF-1, which is regulated by oxygen...
June 2014: Yao Xue Xue Bao, Acta Pharmaceutica Sinica
Lucia Del Vecchio, Francesco Locatelli
INTRODUCTION: Erythropoiesis-stimulating agents (ESA) and iron are the main tools for treating anaemia associated with chronic kidney disease (CKD). Pharmaceutical research has focused on modified epoetins or different strategies to stimulate erythropoiesis with the idea of improving relative disadvantages of the molecules already available in the market. AREAS COVERED: Following a literature search on PubMed using anaemia, haemoglobin, erythropoietin (EPO), hypoxia-inducible transcription factor (HIF) inhibitors and chronic kidney disease as keywords, we critically analysed new strategies for increasing erythropoiesis, looking in depth at their peculiar characteristics and possible advantages in the clinical setting...
May 2014: Expert Opinion on Biological Therapy
Naoharu Takano, Ying-Jie Peng, Ganesh K Kumar, Weibo Luo, Hongxia Hu, Larissa A Shimoda, Makoto Suematsu, Nanduri R Prabhakar, Gregg L Semenza
Increased catalytic activity of CBS (cystathionine β-synthase) was recently shown to mediate vasodilation of the cerebral microcirculation, which is initiated within minutes of the onset of acute hypoxia. To test whether chronic hypoxia was a stimulus for increased CBS expression, U87-MG human glioblastoma and PC12 rat phaeochromocytoma cells were exposed to 1% or 20% O2 for 24-72 h. CBS mRNA and protein expression were increased in hypoxic cells. Hypoxic induction of CBS expression was abrogated in cells transfected with vector encoding shRNA targeting HIF (hypoxia-inducible factor) 1α or 2α...
March 1, 2014: Biochemical Journal
Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Irene Oi-Lin Ng
Hypoxia is a common phenomenon in hepatocellular carcinoma (HCC). Hypoxia stabilizes transcription factor, hypoxia-inducible factor (HIF), to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondary growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis...
March 2014: Frontiers of Medicine
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