Date Published: January 20, 2017
Publisher: Public Library of Science
Author(s): Dieanira Erudaitius, Andrew Huang, Sarah Kazmi, Garry R. Buettner, Victor G. J. Rodgers, Aamir Ahmad.
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.
Recent preclinical studies and a Phase I clinical trial [1–4] 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 . P-AscH- has promise for improving outcomes for pancreatic cancer patients; however, its broad application for other types of cancer has yet to be realized. 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) . 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. Therefore, 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.
While pancreatic cancer cells exhibit significantly reduced proliferation in the presence of extracellular P-AscH- , and normal cells remain unaffected, other cancer cells exhibit a wide variation in susceptibility. Previously, a focus for the underlying differences in susceptibility to P-AscH- has been on the varying catalase activity across cell types [1, 10]. Catalase serves as an intracellular sink for the H2O2 generated by P-AscH-. Our results show that AQP3 acts as a conduit for the flux of H2O2 into the cell . However, a more complete analysis is required for understanding overall flux contributions from variation in permeability to H2O2 as well as catalase activity.