Therapeutics: It's suffocating in here!

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YC-1, a new anticancer drug, can starve tumor cells of the oxygen that is required for growth and metastasis by inhibiting the activity of hypoxia inducible factor-1 alpha (HIF-1 alpha ).

Tumour cells could soon be gasping for breath if promising in vivo results from tests of a new anticancer drug can be extended to the clinic. Park and colleagues have reported that YC-1 — which was originally developed for the treatment of circulatory disorders — can starve tumour cells of the oxygen that is required for growth and metastasis by inhibiting the activity of hypoxia inducible factor-1 alpha (HIF-1 alpha ).

Hypoxia often develops in rapidly growing solid tumours because the growth of new blood vessels cannot keep pace with the increasing size of the tumour. To survive, the tumour must induce factors that promote angiogenesis, such as vascular endothelial growth factor (VEGF). This study is the first to show the in vivo efficacy of targeting HIF-1 alpha , which is a key upstream transcription factor in the angiogenic pathway.

Under normoxic conditions, HIF-1 alpha is hydroxylated, which mediates binding to von Hippel–Lindau protein — a part of the ubiquitin-ligase complex. The subsequent ubiquitylation of HIF-1 alpha leads to its proteasomal degradation. However, under conditions of hypoxia, hydroxylation is inhibited, with the end result that HIF-1 alpha is not degraded. Biologically active HIF-1 alpha increases the level of expression of VEGF.

In vitro results showed that YC-1 inhibits the expression of HIF-1 alpha by tumour cell lines during hypoxia, so the authors tested the in vivo effects of YC-1 in a mouse xenograft model. Nude (immunodeficient) mice were injected with various types of tumour cell line and, once the tumour had become established, were treated daily with YC-1 or placebo. After two weeks, tumour size was significantly smaller in treated mice than in controls, irrespective of tumour type. The level of HIF-1 alpha protein was significantly lower in treated tumours, as were protein and mRNA levels of VEGF. Analysis of tumour sections showed that tumours from YC-1-treated mice had a less-well-developed vasculature and fewer CD31⁺ vessels (CD31 being a marker of endothelial cells).

So, it seems from this initial study that YC-1 could be used to 'suffocate' many types of tumour by preventing their ability to cope with hypoxia. Its low toxicity in the mouse study is an important advantage, although owing to its other known actions in the circulation, possible side effects in humans include increased bleeding time and hypotension.

Kirsty Minton

References

Yeo, E. -J. et al. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J. Natl Cancer Inst. 95, 516–525 (2003) | Article | PubMed |
Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nature Rev. Cancer 2, 727–739 (2002) | Article | PubMed |