Abstract：
BACKGROUND AND PURPOSE:Hypoxia in tumours is known to cause resistance to conventional chemotherapeutic drugs. In contrast, little is known about the effects of hypoxia on targeted anti-cancer drugs. This study evaluated the effect of hypoxia on a series of clinically approved tyrosine kinase inhibitors (TKIs). EXPERIMENTAL APPROACH:The effect of hypoxia (0.1% oxygen) on the activity of conventional cytotoxic drugs (5-fluorouracil, doxorubicin and vinblastine), the hypoxia-activated prodrug tirapazamine and 9 TKIs was determined in a panel of cell lines. Where hypoxia had a marked effect on chemosensitivity, Western blot analysis was conducted to determine the effect of hypoxia on target expression and the effect of TKIs on cell signalling response under aerobic and hypoxic conditions. KEY RESULTS:Three patterns of chemosensitivity were observed: resistance under hypoxia, equitoxic activity against hypoxic and aerobic cells, and preferential cytotoxicity to hypoxic cells. Significant hypoxia selectivity (independent of HIF1) was observed in the case of dasatinib and this correlated with the ability of dasatinib to inhibit phosphorylation of Src at tyrosine 530. Sorafenib was significantly less effective under hypoxic conditions but resistance did not correlate with hypoxia-induced changes in Raf/MEK/ERK signalling. CONCLUSIONS AND IMPLICATIONS:Hypoxia influences the activity of TKIs but in contrast to conventional cytotoxic drugs, preferential activity against hypoxic cells can occur. The search for hypoxia-targeted therapies has been long and fruitless and this study suggests that some clinically approved TKIs could preferentially target the hypoxic fraction of some tumour types.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Ahmadi M,Ahmadihosseini Z,Allison SJ,Begum S,Rockley K,Sadiq M,Chintamaneni S,Lokwani R,Hughes N,Phillips RMdoi
10.1111/bph.12438subject
Has Abstractpub_date
2014-01-01 00:00:00pages
224-36issue
1eissn
0007-1188issn
1476-5381journal_volume
171pub_type
杂志文章abstract：:It has been proposed that the vagus nerve plays a role in mediating cholecystokinin-8 (CCK-8) effect on such gastric functions as motility, emptying and gastric acid secretion. To examine the contribution of the efferent pathways in realizing these effects, efferent mass activity in the ventral gastric vagal nerve in ...
journal_title：British journal of pharmacology
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doi：10.1038/sj.bjp.0703270
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journal_title：British journal of pharmacology
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doi：10.1111/j.1476-5381.1976.tb07661.x
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abstract：:Athletes attempt to improve performance with drugs that act on the beta-adrenergic system directly or indirectly. Of three beta-adrenoceptor (AR) subtypes, the beta(2)-AR is the main target in sport; they have bronchodilator and anabolic actions and enhance anti-inflammatory actions of corticosteroids. Although demons...
journal_title：British journal of pharmacology
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journal_title：British journal of pharmacology
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doi：10.1038/sj.bjp.0702697
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abstract：:1. Whole-cell patch-clamp recordings were made from smooth muscle cells isolated from the longitudinal muscle layer of guinea-pig ileum. Carbachol (acting at muscarinic receptors) or histamine (acting at H1 histamine receptors) suppressed Ca2+ channel current. The effect of either agonist had an initial transient comp...
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doi：10.1038/sj.bjp.0702112
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abstract：BACKGROUND AND PURPOSE:Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids ...
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journal_title：British journal of pharmacology
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doi：10.1111/j.1476-5381.1993.tb14012.x
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journal_title：British journal of pharmacology
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doi：10.1111/j.1476-5381.1988.tb10306.x
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doi：10.1111/j.1476-5381.1994.tb17015.x
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journal_title：British journal of pharmacology
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