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(PP148) Radiosensitivity of prostate carcinoma cells irradiated under normoxic and hypoxic conditions following treatment with HIF inhibitor PX-478.
Palayoor, Sanjeewani*,1, Mitchell, James1, DeGraff, William1, Powis, Garth2, Kirkpatrick, Lynn3, Coleman, C.Norman1, 1 National Cancer Institute, Bethesda, MD, USA2 Arizona Cancer Center, Tucson, AZ, USA3
ABSTRACT- Tumor hypoxia is a major dose limiting factor for radiation therapy. Human tumors overexpress hypoxia inducible transcription factors HIF-1 and HIF-2 as compared to the surrounding normal tissues and overexpression of HIFs in human tumors is associated with poor prognosis and poor outcome to radiation therapy. The purpose of the present study was to investigate if HIF inhibitors can enhance the radiosensitivity of tumor cells. PX-478 (S-2-amino-3-[4 ′-N, N,-bis (2-chloroethyl) amino]-phenyl propionic acid N-oxide dihydrochloride) is a novel agent that suppresses constitutive and hypoxia-induced HIF-1 levels in cancer cells. PX-478 shows antitumor activity against several human tumor xenografts. We studied the effect of PX-478 on HIF-1 protein and radiosensitivity of PC3 and DU-145 human prostate carcinoma cells under normoxic and hypoxic conditions. In clonogenic assay PX-478 reduced the survival of PC3 and DU-145 cells with an IC50 of 18 M and 36 M respectively. In PC3 cells 20 M PX-478 inhibited HIF-1 protein and enhanced radiosensitivity under normoxic condition by a dose modifying factor (DMF) 1.4. In cells treated with PX-478 and irradiated under hypoxic condition, the DMF was 1.56 at 20 M concentration although HIF-1 inhibition was only partial. In DU-145 cells PX-478 inhibited HIF-1 protein and enhanced radiosensitivity at 50 M concentration. The DMF of 50 M PX-478 for normoxic and hypoxic DU-145 cells was 1.21 and 1.25, respectively. Although the mechanism of radiosensitization remains to be identified, these studies suggest a potential role for HIF inhibitors as radiosensitizers. We are currently evaluating the effect of PX-478 on VHL-mutant renal carcinoma cells overexpressing HIFs under normoxic condition and their counterparts which express only basal levels of HIF. These studies will help to understand the significance of HIF in radiation therapy.
Key words: hif-1 alpha, radiosensitivity, hypoxia, px-478
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