High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study

Kishore Polireddy,Gregory Reed,Pierre-Christian Violet,Mark Levine,Stephen Williamson,Ziyan Pessetto,Fang Fan,Ping Chen,Jeanne A Drisko,Ruochen Dong,Qi Chen,Jun Yu,Andrew K Godwin

doi:10.1038/s41598-017-17568-8

Abstract

Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate’s anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

Highlights

There has been increased interest in using high-dose intravenous ascorbate (IVC) as an adjunct therapy with standard chemotherapy[9]
Given the promiscuity of H2O2 as a prodrug for reactive oxygen species (ROS), and the sensitivity of cells to ascorbate despite a variety of mutations, we postulated that pharmacological ascorbate would target multiple pathways in a cancer cell
Previous studies indicate that hydrogen peroxide (H2O2) formation drives the actions of pharmacological ascorbate against cancer cells[19,20,21]

Summary

Introduction

There has been increased interest in using high-dose intravenous ascorbate (IVC) as an adjunct therapy with standard chemotherapy[9]. Two small trials in pancreatic cancer patients were recently reported by Monti et al.[11] and Cullen et al.[12] both using IVC (50–100 g/infusion 2–3x weekly) together with gemcitabine or gemcitabine plus the EGFR inhibitor, erlotinib. In both trials, IVC did not increase any toxicity to the chemotherapy. A recent mechanistic study showed that ascorbate had preferential cytotoxic effects against KRAS and BRAF mutated colon cancer cells[14]. In this study we investigated the mechanisms of Asc in inhibiting pancreatic cancer growth and metastasis, evaluated the safety when adding IVC to gemcitabine chemotherapy, and assessed pharmacokinetics to determine whether there is drug-drug interaction when administering IVC and gemcitabine concurrently

Methods

Results

Conclusion