Hypoxia in tumors: molecular targets for anti-cancer therapeutics

Williams, Kaye J.; Cowen, Rachel L.; Brown, Louisa M.; Chinje, E; Jaffar, Mohammed; Stratford, Ian J.

doi:10.1016/j.advenzreg.2003.11.019

Cited by 16 publications

(11 citation statements)

References 43 publications

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“…The hypothesis that the efficacy of anticancer therapies is limited by the presence of hypoxic tumor cells has resulted in a variety of therapeutic approaches designed to eliminate hypoxic areas, to kill hypoxic cells, or to reduce the treatment resistance of hypoxic cells (7,14,15). The development of hypoxia-targeted therapies has included bioreductive prodrugs, HIF-1 targeting, and genetic engineering of anaerobic bacteria (16)(17)(18). Among these approaches, hypoxia-activated prodrugs (HAPs) are especially promising, because they act via a mechanism involving activation of a nontoxic prodrug selectively in the hypoxic regions of tumors.…”

Section: Introductionmentioning

confidence: 99%

Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

Sun

Liu²,

Wang³

et al. 2012

Clinical Cancer Research

169

164

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Purpose: Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, and metastatic cancer phenotype. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose of this study is to characterize the antitumor activity of TH-302 and investigate its selective targeting of the hypoxic cells in human tumor xenograft models.Experimental Design: Antitumor efficacy was assessed by tumor growth kinetics or by clonogenic survival of isolated cells after tumor excision. Hypoxic fractions (HF) were determined by immunohistochemistry and morphometrics of pimonidazole staining. Tumor hypoxia levels were manipulated by exposing animals to different oxygen concentration breathing conditions. The localization and kinetics of TH-302 induced DNA damage was determined by gH2AX immunohistochemistry.Results: TH-302 antitumor activity was dose-dependent and correlated with total drug exposure. Correlation was found between antitumor activity and tumor HF across 11 xenograft models. Tumorbearing animals breathing 95% O 2 exhibited attenuated TH-302 efficacy, with whereas those breathing 10% O 2 exhibited enhanced TH-302 efficacy, both compared with air (21% O 2 ) breathing. TH-302 treatment resulted in a reduction in the volume of the HF 48 hours after dosing and a corresponding increase in the necrotic fraction. TH-302 induced DNA damage as measured by gH2AX was initially only present in the hypoxic regions and then radiated to the entire tumor in a time-dependent manner, consistent with TH-302 having a "bystander effect."Conclusions: The results show that TH-302 has broad antitumor activity and selectively targets hypoxic tumor tissues. Clin Cancer Res; 18(3); 758-70. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

Sun

Liu²,

Wang³

et al. 2012

Clinical Cancer Research

169

164

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“…Hypoxia environment is commonly found in solid tumors, including hepatocellular carcinoma, which resulted from imbalance of the high proliferation rate of tumor cells and abnormal vascularization [43]. Previous reports showed hypoxia play a crucial role in metabolism, stemness and EMT phenotype [6].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Liu¹,

Tu²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1α expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated. Methods: HCC cells were cultured under controlled hypoxia conditions or normoxic conditions. Transwell assays were used to examine the migration and invasion capacity. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. Results: In present study, we first observed a strongly positive correlation between HIF-1α and GLI1 expression in HCC tissues. Then, we showed that hypoxia significantly promoted EMT process and invasion of HCC cells, associated with activating the non-canonical Hh pathway without affecting SHH and PTCH1 expression. HIF-1α knockdown mitigated hypoxia-induced SMO and GLI1 expression, EMT invasion of HCC cells. Moreover, the SMO inhibitor or GLI1 siRNA also reversed the hypoxia-driven EMT and invasion of HCC cells under hypoxia condition. Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in HCC cells. In addition, we found that hypoxia increased ROS production and that ROS inhibitors (NAC) blocked GLI1-dependent EMT process and invasion under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is involved in hypoxia-induced ROS production. NOX4 expression was found to be increased at both mRNA and protein levels in hypoxic HCC cells. Furthermore, siRNA-mediated knockdown of NOX4 expression abolished hypoxia induced ROS generation and GLI1-dependent activation and invasion of HCC cells. Conclusion: Our findings indicate that hypoxia triggers ROS-mediated GLI1-dependent EMT progress and invasion of HCC cells through induction of NOX4 expression. Thus, hypoxia-driven ROS mediated non-canonical Hh signaling may play an important role in the initiation of EMT and provides a potential marker for cancer prevention and treatment.

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“…The pattern of hypoxia in tumors is dynamic with both temporal and spatial variations. Clinical studies indicate that extensive hypoxia in human tumors correlates with poor prognosis (21)(22)(23)(24), reflecting not only the radioresistance of hypoxic cancer cells but also a more aggressive phenotype.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner

Gibson

Bindra²,

Glazer³

2005

Cancer Research

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Chk2 is a serine/threonine kinase that signals to cell cycle arrest, DNA repair, and apoptotic pathways following DNA damage. It is activated by phosphorylation in response to ionizing radiation, UV light, stalled replication forks, and other types of DNA damage. Hypoxia is a common feature of solid tumors and has been shown to affect the regulation of many genes, including several DNA repair factors. We show here that Chk2 is phosphorylated on Thr68 and thereby activated in cells in response to hypoxia, and that this phosphorylation is dependent on the damage response kinase ataxia telangiectasia mutated (ATM) but not on the related kinase ATM and Rad3-related. Moreover, phosphorylation of Chk2 under hypoxia was attenuated in cells deficient in the repair factors MLH1 or NBS1. Finally, Chk2 serves to protect cells from apoptosis under hypoxic growth conditions. These results identify hypoxia as a new stimulus for Chk2 activation in an ATM-, MLH1-, and NBS1-dependent manner, and they suggest a novel pathway by which tumor hypoxia may influence cell survival and DNA repair.

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Hypoxia in tumors: molecular targets for anti-cancer therapeutics

Cited by 16 publications

References 43 publications

Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

Selective Tumor Hypoxia Targeting by Hypoxia-Activated Prodrug TH-302 Inhibits Tumor Growth in Preclinical Models of Cancer

Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling

Hypoxia-Induced Phosphorylation of Chk2 in an Ataxia Telangiectasia Mutated–Dependent Manner

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