Abstract
Angiostatin is a naturally occurring inhibitor of angiogenesis that is being developed as a drug to fight cancer. In this study we reveal that EL-4 tumors established in mice rapidly develop resistance to angiostatin gene therapy by upregulating hypoxia-inducible pathways. Angiostatin initially delayed tumor growth for 6 days by reducing blood vessel density. However, tumors quickly responded by upregulating the production of hypoxia-inducible factor-1α (HIF-1α) and its effector vascular endothelial growth factor (VEGF) in response to increasing tumor hypoxia, leading to restored angiogenesis and rapid tumor growth. Theoretically, blockade of HIF-1 should prevent resistance to anti-angiogenic therapy by preventing a tumor from responding to induced hypoxia. Antisense HIF-1α inhibited the expression of HIF-1α and of the HIF-1 effectors VEGF, glucose transporter-1 and lactate dehydrogenase. As a monotherapy, it was effective in eradicating small 0.1 cm diameter tumors, but only delayed the growth of large 0.4 cm diameter tumors. In contrast, timed injection of a combination of angiostatin and antisense HIF-1α plasmids completely eradicated large EL-4 tumors within 2 weeks, and prevented upregulation of hypoxia-inducible pathways induced by angiostatin. The data indicate that blocking hypoxia-inducible pathways by antisense HIF-1α can circumvent hypoxia-induced drug resistance and thereby augment the efficacy of anti-angiogenic therapies.
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Acknowledgements
This work was supported by grants from the Wellcome Trust (UK), the World Health Organization, the Royal Society of New Zealand, the Cancer Society of New Zealand, the Health Research Council of New Zealand, the Lottery Grants Board of New Zealand, the Maurice and Phyllis Paykel Trust and the National Natural Scientific Foundation of China (30872987 and 30973474). GWK was supported by a James Cook Research Fellowship funded by the Royal Society of New Zealand. XS was supported by a Wellcome Trust Research Leave Fellowship.
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Sun, X., Vale, M., Jiang, X. et al. Antisense HIF-1α prevents acquired tumor resistance to angiostatin gene therapy. Cancer Gene Ther 17, 532–540 (2010). https://doi.org/10.1038/cgt.2010.7
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DOI: https://doi.org/10.1038/cgt.2010.7
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