Utilization of redox modulating small molecules that selectively act as pro-oxidants in cancer cells to open a therapeutic window for improving cancer therapy

Abstract

There is a rapidly growing body of literature supporting the notion that differential oxidative metabolism in cancer versus normal cells represents a metabolic frailty that can be exploited to open a therapeutic window into cancer therapy. These cancer cell-specific metabolic frailties may be amenable to manipulation with non-toxic small molecule redox active compounds traditionally thought to be antioxidants. In this review we describe the potential mechanisms and clinical applicability in cancer therapy of four small molecule redox active agents: melatonin, vitamin E, selenium, and vitamin C. Each has shown the potential to have pro-oxidant effects in cancer cells while retaining antioxidant activity in normal cells. This dichotomy can be exploited to improve responses to radiation and chemotherapy by opening a therapeutic window based on a testable biochemical rationale amenable to confirmation with biomarker studies during clinical trials. Thus, the unique pro-oxidant/antioxidant properties of melatonin, vitamin E, selenium, and vitamin C have the potential to act as effective adjuvants to traditional cancer therapies, thereby improving cancer patient outcomes.

Characterization of Stress Responses in a Drosophila Model of Werner Syndrome

“…Vitamin C treatment resulted in no difference in lifespan between starved w 1118 and WRNexo Δ females, which suggests that higher body fat rescued starvation sensitivity in WRNexo Δ compared to w 1118 ( Figure 3 B). However, an alternate explanation may lie in our observed vitamin C toxicity: Vitamin C treatment resulted in a shorter lifespan for all genotypes, possibly owing to its pro-oxidant qualities at high doses [ 51 , 52 ]. However, WRNexo Δ flies were less affected by vitamin C toxicity as shown by a smaller difference in lifespan between untreated and vitamin C-treated flies.…”

“…While vitamin C also reduced lifespan in male flies, starvation sensitivity was unaffected (Figure S9). shorter lifespan for all genotypes, possibly owing to its pro-oxidant qualities at high doses [51,52]. However, WRNexo Δ flies were less affected by vitamin C toxicity as shown by a smaller difference in lifespan between untreated and vitamin C-treated flies.…”

The Role of Selenium in Pathologies: An Updated Review

“…Other functions include the modulation of gene expression, the redox and hormonal regulation of metabolism, and a role in DNA repairing and cell-signalling pathways. Selenoproteins act at different pivotal levels: they inhibit cell proliferation, stimulate apoptosis, and reduce metastasis arresting the cell cycle in the G1 phase, via the redox modification of protein-thiols, and methionine mimicry in critical proteins ( Figure 2 ) [ 56 , 57 , 58 ]. Selenoproteins that are directly or indirectly linked to redox homeostasis maintenance, such as GPXs, TXNRD1, SELENOF, and SELENOP appear to affect multiple signalling pathways involved in cancer initiation and progression.…”

“…Their possible role in inhibiting neo-angiogenesis of activated endothelial cells has also been reported. Indeed, precursors of methylselenol have been shown to inhibit the expression of vascular endothelial matrix metalloproteinase-2 and growth factor in cancer cells [ 56 , 58 ].…”

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

“…During standard RT treatment for brain cancers such as fractionated partial- and whole-brain radiation treatment (PBRT and WBRT), healthy brain tissue is inevitably exposed, resulting in side effects, such as learning and cognitive deficits, including memory impairment, neurological deficits, increased intracranial pressure, and progressive dementia [ 47 , 48 , 49 , 50 ]. Therefore, the indiscriminate nature of RT-induced ROS and cellular damage underscores the necessity for developing therapies, such as P-AscH − , to selectively enhance the effects of radiation on cancer cells, while simultaneously protecting normal tissues from RT-induced toxicity [ 51 ].…”