Peroxiporin Expression Is an Important Factor for Cancer Cell Susceptibility to Therapeutic H2O2: Implications for Pharmacological Ascorbate Therapy

Dieanira Erudaitius,Garry R Buettner,Victor G J Rodgers,Andrew Huang,Sarah Kazmi,Aamir Ahmad

doi:10.1371/journal.pone.0170442

Dieanira Erudaitius, Garry R Buettner + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0170442

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Abstract

Cancer cell toxicity to therapeutic H2O2 varies widely depending on cell type. Interestingly, it has been observed that different cancer cell types have varying peroxiporin expression. We hypothesize that variation in peroxiporin expression can alter cell susceptibility to therapeutic H2O2 concentrations. Here, we silence peroxiporin aquaporin-3 (AQP3) on the pancreatic cancer cell line MIA PaCa-2 and compare clonogenic survival response to the wild-type. The results showed a significantly higher surviving fraction in the clonogenic response for siAQP3 MIA PaCa-2 cells at therapeutic H2O2 doses (P < 0.05). These results suggest that peroxiporin expression is significant in modulating the susceptibility of cancer cells to ascorbate therapy.

Highlights

Recent preclinical studies and a Phase I clinical trial [1,2,3,4] have demonstrated promise in the use of the pro-drug pharmacological ascorbate (P-AscH-) as an adjuvant in the treatment of pancreatic ductal adenocarcinoma
Quantification shows the variation in expression of each of the AQPs between the two cell-types providing insight as to which peroxiporin is more highly expressed by MIA PaCa-2 cancer cells, Fig 1
AQP8 has a higher expression in MIA PaCa-2 compared to H6c7 cells, it is clear that AQP3 is significantly more elevated in MIA PaCa-2 cells compared to H6c7 cells

Summary

Introduction

Recent preclinical studies and a Phase I clinical trial [1,2,3,4] have demonstrated promise in the use of the pro-drug pharmacological ascorbate (P-AscH-) as an adjuvant in the treatment of pancreatic ductal adenocarcinoma. Intravenous infusions of P-AscH- (plasma concentrations of %20 mM) decreased tumor volume and suggested increased survival of patients with stage 4 pancreatic cancer [3]. The impotence in moving forward with P-AscH- therapy for patients with other types of cancer is due, in part, to observations in a recent in vitro study by Chen et al (2008) [5]. There, they reported that while normal cells remain relatively unaffected to P-AscH-, cancer cell lines exhibit a wide range of responses as seen by rates of clonogenic survival. It is of great interest to understand why certain cancer cells are more responsive to P-AscH- and thereby guide the use of P-AscH- as an adjuvant to cancer therapy

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