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Prostate cancer cells can exist in a hypoxic microenvironment, causing radioresistance. Nitric oxide (NO) is a radiosensitiser of mammalian cells. NO-NSAIDs are a potential means of delivering NO to prostate cancer cells. This study aimed to determine the effect and mechanism of action of NO-sulindac and radiation, on prostate cancer cells and stroma, under normoxia (21% oxygen) and chronic hypoxia (0.2% oxygen). Using clonogenic assays, at a surviving fraction of 10% the sensitisation enhancement ratios of radiation plus NO-sulindac over radiation alone on PC-3 cells were 1.22 and 1.42 under normoxia and hypoxia, respectively. 3D culture of PC-3 cells revealed significantly reduced sphere diameter in irradiated spheres treated with NO-sulindac.
Neither NO-sulindac nor sulindac radiosensitised prostate stromal cells under normoxia or hypoxia. HIF-1α protein levels were reduced by NO-sulindac exposure and radiation at 21% and 0.2% oxygen. Alkaline Comet assay analysis suggested an increased rate of single strand DNA breaks and slower repair of these lesions in PC-3 cells treated with NO-sulindac prior to irradiation. There was a higher level of γ-H2AX production and hence double strand DNA breaks following irradiation of NO-sulindac treated PC-3 cells. At all radiation doses and oxygen levels tested, treatment of 2D and 3D cultures of PC-3 cells with NO-sulindac prior to irradiation radiosensitised PC-3, with minimal effect on stromal cells.
Hypoxia response inhibition and increased DNA double strand breaks are potential mechanisms of action. Neoadjuvent and concurrent use of NO-NSAIDs have the potential to improve radiotherapy treatment of prostate cancer under normoxia and hypoxia.
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In spite of these key differences, NO enhances
the yields of radiation-induced SSBs and DSBs (this study & ), as do oxygen and
nitroimidazoles . The mechanism of the NO-mediated enhancement of strand
break is not clear, but might involve the attempted repair processing/excision of the
adducted base; indeed, this may account for the noted slower repair of both SSB (this
study) and DSB  for cells irradiated in the presence of NO or NO-sulindac
compared with cells irradiated in air (this study) or anoxia . Overall, the
radiobiological assay results presented above further support the discovery that NOsulindac
radiosensitises PC-3 cells.
In summary, these 2D and 3D studies have shown that NO-sulindac
radiosensitises prostate cancer epithelial cells but not prostate stromal cells in vitro,
under normoxia and to a greater extent chronic hypoxia. Plausible mechanisms for
this effect being the enhanced formation and reduced repair of radiation-induced
DNA strand breaks and inhibition of the radioresistant hypoxia response. These data
and that from other studies  lend support to future clinical trials of NO-sulindac
plus radiotherapy in men with prostate cancer.
Ultimately, NO-NSAIDs and other
NO-donors may be useful as neoadjuvant and concurrent treatments for men
undergoing radiotherapy for prostate cancer.
Keywords: hypoxia; prostate cancer; nitric oxide donors; radiation; radiosensitisation