HIF-1\u03b1- Targeting Acriflavine Provides Long Term Survival and Radiological Tumor Response in Brain Cancer Therapy

Antonella Mangraviti,Michael Peters,Riccardo Serra,Francesco Volpin,Jinyuan Zhou,Alessandro Olivi,Fausto J Rodríguez ,Ann Liu,Tula Raghavan,Laura Asnaghi,Noah Gorelick,Eric W Sankey ,Dong Hoon Lee ,Nicolas Skuli,Henry Brem,Charles G Eberhart,David Gullotti,Yuan Wang,Destiny Schriefer,Fabien Delaspre,Betty Tyler

doi:10.1038/s41598-017-14990-w

Abstract

Tumor progression, limited efficacy of current standard treatments, and the rise in patient mortality are associated with gene expression caused by the synergistic action of intratumoral hypoxia and HIF-1α activation. For this reason, recent investigations have focused on HIF-targeting therapeutic agents, with encouraging preclinical and clinical results in solid tumors. Here we describe the efficacy of a HIF-1α inhibitor, Acriflavine, and demonstrate its potency against brain cancer. This safe antibacterial dye induces cell death and apoptosis in several glioma cell lines, targets HIF-1α–mediated pathways, and decreases the level of PGK1, VEGF and HIF-1α in vitro and in vivo. Administered locally via biodegradable polymers, Acriflavine provides significant benefits in survival resulting in nearly 100% long term survival, confirmed by MRI and histological analyses. This study reports preclinical evidence that this safe, small molecule can contribute to brain tumor therapy and highlights the significance of HIF-1α-targeting molecules.

Highlights

This study presents a new hypoxia-inducible factors (HIFs)-1-targeting therapy developed for brain tumor treatment using intratumorally delivered Acriflavine (ACF), an inexpensive, FDA-approved small molecule with HIF-1-inhibiting properties[20]
To investigate the efficacy of ACF against brain tumor cancer cells, the drug was tested in several glioma models, including historically established experimental rodent and human glioma cell lines (F98, 9L, GL261, U87) as well as human primary brain tumor stem cells (BTSCs), including both adherent cell lines and neurospheres
To evaluate whether the inhibition of glioma cell proliferation was attributed to apoptosis induced by ACF, we examined apoptotic profiles in 9L, F98, U87, GL261 and the two brain tumor stem cell lines (BTSCs) lines using Annexin –V/Propidium Iodide flow cytometric analysis

Summary

Introduction

This study presents a new HIF-1-targeting therapy developed for brain tumor treatment using intratumorally delivered Acriflavine (ACF), an inexpensive, FDA-approved small molecule with HIF-1-inhibiting properties[20]. The effects of ACF on cancer cells were first reported 50 years ago[22], but research interest peaked in 2009, when a study of 336 drugs singled out ACF as the most potent HIF-1α inhibitor with effective tumor growth inhibition in a prostate cancer model[20]. Further investigations of this small molecule resulted in highly promising antitumor activity against a wide spectrum of cancers, including colorectal[23], perihilar cholangiocarcinomas[24], hepatocellular[25], and ovarian and chronic lymphocytic leukemia cancer cell lines[26]. Our findings introduce locally delivered ACF as an effective and promising therapeutic option and show that HIF-1α-targeting molecular therapy has the potential to mark a new step forward in the treatment of brain cancer

Methods

Results

Conclusion