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Inhibition of hypoxia-inducible factors limits tumor progression in a mouse model of colorectal cancer.

Carcinogenesis (2014-01-11)
Jessica E S Shay, Hongxia Z Imtiyaz, Sharanya Sivanand, Amy C Durham, Nicolas Skuli, Sarah Hsu, Vera Mucaj, T S Karin Eisinger-Mathason, Bryan L Krock, Dionysios N Giannoukos, M Celeste Simon
ABSTRACT

Hypoxia-inducible factors (HIFs) accumulate in both neoplastic and inflammatory cells within the tumor microenvironment and impact the progression of a variety of diseases, including colorectal cancer. Pharmacological HIF inhibition represents a novel therapeutic strategy for cancer treatment. We show here that acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity, halts the progression of an autochthonous model of established colitis-associated colon cancer (CAC) in immunocompetent mice. ACF treatment resulted in decreased tumor number, size and advancement (based on histopathological scoring) of CAC. Moreover, ACF treatment corresponded with decreased macrophage infiltration and vascularity in colorectal tumors. Importantly, ACF treatment inhibited the hypoxic induction of M-CSFR, as well as the expression of the angiogenic factor (vascular endothelial growth factor), a canonical HIF target, with little to no impact on the Nuclear factor-kappa B pathway in bone marrow-derived macrophages. These effects probably explain the observed in vivo phenotypes. Finally, an allograft tumor model further confirmed that ACF treatment inhibits tumor growth through HIF-dependent mechanisms. These results suggest pharmacological HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, purified by ion-exchange chromatography, TLR ligand tested
Sigma-Aldrich
Acriflavine
Sigma-Aldrich
Acriflavine, BioReagent, suitable for fluorescence, ≥90% (AT)
Sigma-Aldrich
ApopTag Plus In Situ Apoptosis Fluorescein Detection Kit, The ApopTag Plus Fluorescein In Situ Apoptosis Detection Kit detects apoptotic cells in situ by the indirect TUNEL method, utilizing an anti-digoxigenin antibody that is conjugated to a fluorescein reporter molecule.

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