Hypoxia Induced Resistance to Doxorubicin in Prostate Cancer Cells is Inhibited by Low Concentrations of Glyceryl Trinitrate

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Abstract
Purpose: Tumor hypoxia has been correlated with metastasis and resistance to chemotherapy. Hypoxia is also associated with human prostate cancers, which are highly resistant to chemotherapy. We hypothesized that hypoxia contributes to chemoresistance in prostate cancer cells and this hypoxia induced chemoresistance can be inhibited by low concentrations of nitric oxide (NO) mimetics. Materials and Methods: Human PC-3 and mouse TRAMP-C2 prostatic adenocarcinoma cells were incubated in 20% or 0.5% O2 for 12 hours with or without glyceryl trinitrate (GTN) (0.1 nM). This treatment was followed by a 1-hour incubation with doxorubicin and survival was assessed by clonogenic assays. Western blot analysis was used to measure NO synthase levels. The effect of hypoxia and GTN on cell cycle distribution was determined by flow cytometry. Results: Hypoxic pre-incubation of the 2 cell lines resulted in increased survival following exposure to doxorubicin. Co-incubation of PC-3 and TRAMP-C2 cells with GTN (0.1 nM) inhibited the hypoxia induced resistance to doxorubicin. Each cell line expressed all 3 NO synthase isoforms at levels that were not significantly affected by O2 concentrations. Cell cycle analysis revealed that there was no significant difference in the distribution of PC-3 cells at each stage of the cycle. However, incubation under hypoxia resulted in a small decrease in the number of TRAMP-C2 cells in S-phase. Conclusions: These findings indicate that NO may have an important role in the regulation of chemosensitivity in prostate cancer cells. Furthermore, the results suggest that GTN administration may represent a means of chemosensitizing prostatic carcinomas.