These authors contributed equally to this work.
Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors
Article first published online: 10 DEC 2013
© 2013 The British Pharmacological Society
British Journal of Pharmacology
Volume 171, Issue 1, pages 224–236, January 2014
How to Cite
Ahmadi, M., Ahmadihosseini, Z., Allison, S. J., Begum, S., Rockley, K., Sadiq, M., Chintamaneni, S., Lokwani, R., Hughes, N. and Phillips, R. M. (2014), Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors. British Journal of Pharmacology, 171: 224–236. doi: 10.1111/bph.12438
- Issue published online: 10 DEC 2013
- Article first published online: 10 DEC 2013
- Accepted manuscript online: 4 OCT 2013 04:05AM EST
- Manuscript Accepted: 23 SEP 2013
- Manuscript Revised: 23 AUG 2013
- Manuscript Received: 25 APR 2013
- Yorkshire Cancer Research. Grant Number: BPP028
- tyrosine kinase inhibitors;
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).
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.
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.