Inhibitors of HIF-1α and CXCR4 Mitigate the Development of Radiation Necrosis in Mouse Brain

Publication date: Available online 21 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ruimeng Yang, Chong Duan, Liya Yuan, John A. Engelbach, Christina I. Tsien, Scott C. Beeman, Carlos J. Perez-Torres, Xia Ge, Keith M. Rich, Joseph J.H. Ackerman, Joel R. Garbow
PurposeThere is mounting evidence that, in addition to angiogenesis, hypoxia-induced inflammation via the hypoxia inducible factor-1α (HIF-1α) / CXC chemokine receptor-4 (CXCR4) pathway may also contribute to the pathogenesis of late-onset, radiation-induced necrosis (RN). The present study investigates the mitigative efficacy of a HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of RN in an intracranial mouse model.Methods and MaterialsMice received a single-fraction, 50-Gy dose of hemispheric radiation from the Leksell GammaKnife® PerfexionTM and were then treated with either topotecan, a HIF-1α inhibitor, from 1-12 weeks post-irradiation (PIR), or AMD3100, a CXCR4 antagonist, from 4-12 weeks PIR. The onset and progression of RN were monitored longitudinally via noninvasive, in vivo MRI from 4-12 weeks PIR. Conventional hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) staining were performed to evaluate the treatment response.ResultsThe progression of brain RN was significantly mitigated for mice treated with either topotecan or AMD3100, compared to control animals. MR-derived lesion volumes were significantly smaller for both of the treated groups, and histologic findings correlated well with the MRI data. By H&E staining, both treated groups demonstrated reduced radiation-induced tissue damage compared with controls. Further, IHC results revealed that expression levels of VEGF, CXCL12, CD-68, CD3 and TNF-α in the lesion area were significantly lower in treated (topotecan or AMD3100) brains vs. control brains, while Iba-1 and HIF-1α expression was similar, though somewhat reduced. CXCR4 expression was reduced only in topotecan-treated mice, while IL-6 expression was unaffected by either topotecan or AMD3100.ConclusionsBy reducing inflammation, both topotecan and AMD3100 can, independently, mitigate the development of RN in mouse brain. When combined with first-line, anti–angiogenic treatment, anti-inflammation therapy may provide an adjuvant therapeutic strategy for clinical, post-radiation management of tumors, with additional benefits in the mitigation of RN development.

Teaser

The efficacy of a HIF-1α inhibitor, topotecan, and a CXCR4 antagonist, AMD3100, on the development of radiation necrosis was investigated in an intracranial mouse model. Mice were irradiated with the Leksell GammaKnife^® Perfexion^TM, and the development and progression of radiation necrosis were monitored longitudinally in vivo using magnetic resonance imaging, supported with correlative histology. Both topotecan and AMD3100 can, independently, mitigate the development of RN in mouse brain by reducing inflammation.


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