460 MP-Pt(IV): A Platinum (IV)-Based Prodrug for Treating DIPG With Selective Mitochondrial Chemotherapy

Abstract

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. We previously developed MP-Pt(IV), a platinum (IV) based prodrug that is selectively accumulates in GBM mitochondria upon oxidation by the overexpressed enzyme monoamine oxidase B (MAOB), and is then reduced to the chemotherapeutic cisplatin. Expression levels of MAOB in DIPG is high. METHODS: In-vitro cell growth inhibition studies were conducted on DIPG cells using MP-Pt(IV). Labeling studies were carried out with Mitosox, Mitotraker, and H2DCF. Oxygen consumption studies were performed to show mitochondrial targeting. Clonogenic survival assay and scratch assay were performed. RESULTS: MP-Pt(IV) shows potent growth inhibition of DIPG in cell culture studies. Mechanistic studies indicate mitochondrial targeting of the prodrug. Significant increases in cellular ROS and hydrogen peroxide levels are observed upon MP-Pt(IV) treatment. Oxygen consumption studies confirm mitochondrial targeting of MP-Pt(IV). MP-Pt(IV) strongly inhibits clonogenic survival and cell migration in treated cells. CONCLUSIONS: We demonstrate that MP-Pt(IV) is highly effective in DIPG in vitro, and is a good candidate for testing in an in-vivo mouse intracranial DIPG model, and for further development.