Pathophysiological Response to Hypoxia — From the Molecular Mechanisms of Malady to Drug Discovery: Drug Discovery for Targeting the Tumor Microenvironment

Nagasawa, Hideko

doi:10.1254/jphs.10r25fm

Cited by 15 publications

(15 citation statements)

References 30 publications

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“…As suggested for NF-κB and STAT-3, HIF-1 might be a potential target in hepatocellular carcinoma therapy (296). HIF-1 has been also proposed as a key molecule implicated in tumor metastasis (297, 298) and a possible metabolic target in cancer therapy (299–301). Inflammatory molecules like TNF-α are also secreted by adipose tissue in response to hypoxia and macrophage–monocyte infiltration (280).…”

Section: Pathophysiological Mechanisms Relating Visceral Adipose Tissmentioning

confidence: 99%

Mechanisms Linking Excess Adiposity and Carcinogenesis Promotion

et al. 2014

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Obesity constitutes one of the most important metabolic diseases being associated to insulin resistance development and increased cardiovascular risk. Association between obesity and cancer has also been well established for several tumor types, such as breast cancer in post-menopausal women, colorectal, and prostate cancer. Cancer is the first death cause in developed countries and the second one in developing countries, with high incidence rates around the world. Furthermore, it has been estimated that 15–20% of all cancer deaths may be attributable to obesity. Tumor growth is regulated by interactions between tumor cells and their tissue microenvironment. In this sense, obesity may lead to cancer development through dysfunctional adipose tissue and altered signaling pathways. In this review, three main pathways relating obesity and cancer development are examined: (i) inflammatory changes leading to macrophage polarization and altered adipokine profile; (ii) insulin resistance development; and (iii) adipose tissue hypoxia. Since obesity and cancer present a high prevalence, the association between these conditions is of great public health significance and studies showing mechanisms by which obesity lead to cancer development and progression are needed to improve prevention and management of these diseases.

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Section: Pathophysiological Mechanisms Relating Visceral Adipose Tissmentioning

confidence: 99%

Mechanisms Linking Excess Adiposity and Carcinogenesis Promotion

et al. 2014

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“…Finally, HIF-1a was associated with an increase occurrence of metastases. Furthermore HIF-1a inhibition might improve sensitivity of tumors to radiation 37,41.…”

Section: Introductionmentioning

confidence: 99%

Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation

et al. 2016

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Adipose tissue in addition to its ability to keep lipids is now recognized as a real organ with both metabolic and endocrine functions. Recent studies demonstrated that in obese animals is established a status of adipocyte hypoxia and in this hypoxic state interaction between adipocytes and stromal vascular cells contribute to tumor development and progression. In several tumors such as breast, colon, liver and prostate, obesity represents a poor predictor of clinical outcomes. Dysfunctional adipose tissue in obesity releases a disturbed profile of adipokines with elevated levels of pro-inflammatory factors and a consequent alteration of key signaling mediators which may be an active local player in establishing the peritumoral environment promoting tumor growth and progression. Therefore, adipose tissue hypoxia might contribute to cancer risk in the obese population. To date the precise mechanisms behind this obesity-cancer link is not yet fully understood. In the light of information provided in this review that aims to identify the key mechanisms underlying the link between obesity and cancer we support that inflammatory state specific of obesity may be important in obesity-cancer link.

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“…More recently, the hypoxic microenvironment has been proposed to provide the cancer stem cell a niche conducive to the maintenance of stem cell characteristics 1,2. The TME has attracted attention over the years and has emerged as a critical target for cancer therapy, independent of cancer type 3,4. Although considerable attention has been paid to targeting hypoxia inducible factor (HIF)-1 in drug discovery, most HIF-1 inhibitors have been shown to exhibit no specificity for the HIF-1 molecule.…”

Section: Introductionmentioning

confidence: 99%

“…We regarded the adaptive cellular responses against multiple microenvironmental stresses, such as hypoxia and nutrition deprivation, as a critical survival strategy for malignant tumor cells and a potential drug target for cancer treatment. Accordingly, we engaged in the development of an antitumor drug targeting the microenvironmental stress responses as a TME modulator 4,6…”

Section: Introductionmentioning

confidence: 99%

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Narise

Okuda

Enomoto

et al. 2014

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Adaptive cellular responses resulting from multiple microenvironmental stresses, such as hypoxia and nutrient deprivation, are potential novel drug targets for cancer treatment. Accordingly, we focused on developing anticancer agents targeting the tumor microenvironment (TME). In this study, to search for selective antitumor agents blocking adaptive responses in the TME, thirteen new compounds, designed and synthesized on the basis of the arylmethylbiguanide scaffold of phenformin, were used in structure activity relationship studies of inhibition of hypoxia inducible factor (HIF)-1 and unfolded protein response (UPR) activation and of selective cytotoxicity under glucose-deprived stress conditions, using HT29 cells. We conducted luciferase reporter assays using stable cell lines expressing either an HIF-1-responsive reporter gene or a glucose-regulated protein 78 promoter-reporter gene, which were induced by hypoxia and glucose deprivation stress, respectively, to screen for TME-targeting antitumor drugs. The guanidine analog (compound 2), obtained by bioisosteric replacement of the biguanide group, had activities comparable with those of phenformin (compound 1). Introduction of various substituents on the phenyl ring significantly affected the activities. In particular, the o-methylphenyl analog compound 7 and the o-chlorophenyl analog compound 12 showed considerably more potent inhibitory effects on HIF-1 and UPR activation than did phenformin, and excellent selective cytotoxicity under glucose deprivation. These compounds, therefore, represent an improvement over phenformin. They also suppressed HIF-1- and UPR-related protein expression and secretion of vascular endothelial growth factor-A. Moreover, these compounds exhibited significant antiangiogenic effects in the chick chorioallantoic membrane assay. Our structural development studies of biguanide derivatives provided promising candidates for a novel anticancer agent targeting the TME for selective cancer therapy, to be subjected to further in vivo study.

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Pathophysiological Response to Hypoxia — From the Molecular Mechanisms of Malady to Drug Discovery: Drug Discovery for Targeting the Tumor Microenvironment

Cited by 15 publications

References 30 publications

Mechanisms Linking Excess Adiposity and Carcinogenesis Promotion

Mechanisms Linking Excess Adiposity and Carcinogenesis Promotion

Obesity and cancer: the role of adipose tissue and adipo-cytokines-induced chronic inflammation

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

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