Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy

Abstract

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue.

Magnetite nanoparticles as a kinetically favorable source of iron to enhance GBM response to chemoradiosensitization with pharmacological ascorbate

“…A single clone was used for this work. Similarly, catalase overexpression in this clone was confirmed using a catalase activity assay [ 34 ]. Catalase overexpression was achieved by treating cells with doxycycline (1 μg mL −1 ) for 48 h before experimentation.…”

“…Cells were treated for 1 h with AscH − (20 pmol cell −1 ; ≈ 8–10 mM), Fe 3+ -EDTA (50 μM), or FMX (20 μg mL −1 ; ≈2.75 nM) in complete cell culture media without FBS or Na-pyruvate to prevent scavenging of H 2 O 2 . U87 glioblastoma cells underwent lentiviral transduction for doxycycline-inducible catalase overexpression as previously described [ 34 ]. A single clone was used for this work.…”

Pharmacological ascorbate as a novel therapeutic strategy to enhance cancer immunotherapy

“…Multiple studies by Levine and colleagues then confirmed that for cancer cell killing to be accomplished, pharmacological doses of ascorbate are required as they lead to the generation of toxic concentrations of hydrogen peroxide in the extracellular space in the tumor but not in the blood leading to selective killing ( 92 – 94 ). These findings initiated a new wave of ascorbate research in cancer therapy in the early 2000s ( 7 , 95 – 100 ).…”

Reactive oxygen species in the progression and treatment of malignant mesothelioma

“…Additional studies have shown that some ROS-inducing agents may be able to sensitize cancer cells to treatments like radiation therapy. One, in particular, is vitamin C (ascorbate) which acts as a pro-oxidant at higher doses [86] and has been shown to enhance sensitivity to radiation therapy in pancreatic cancer [87,88] . Other studies have shown that depletion of arginine, a critical amino acid in the biosynthesis of proteins, nitric oxide, and polyamine is an actionable approach for therapeutic intervention in argininosuccinate synthase I (ASSI) -negative tumors, including MM [89,90] .…”