Relationship of oral glycine with radiation-induced HIF1-alpha and tumor growth delay in a prostate cancer xenograft.
81 Background: Preclinical studies have shown that nitric oxide (NO) is produced by upregulation of inducible nitric oxide synthase (iNOS) in activated macrophages recruited to the site of cytotoxic injury from radiation or chemotherapy. NO stabilizes hypoxia-inducible factor 1-alpha (HIF1α), leading to increased vascular endothelial growth factor, thus promoting tumor angiogenesis as a recovery mechanism from the initial cytotoxic insult. Because glycine (G) suppresses macrophage activation, we hypothesized that dietary supplementation with G would inhibit HIF1α expression and enhance tumor growth delay by preventing recovery angiogenesis. METHODS: PC3 cells were transfected with a HIF1α-inducible luciferase reporter and grown as nude mice xenografts. As tumors grew to 100mm(3), mice were continued in 1 of 4 conditions: 1) control (C) diet ; 2) a 5%G diet; 3) C diet with ad libitum drinking water treated with L-NAME (500mg/L), an iNOS inhibitor; or 4) C diet with a single injection of carrageenan (2mg/500uL), a selective macrophagicidal agent. After 3 days tumors were irradiated with 0 Gy (sham) or 6 Gy using a 160kV source. Tumor growth and quantitative bioluminescence data were then collected (n = 4 mice/group). RESULTS: HIF1α expression as assessed by bioluminescence increased more than two fold 4-6 days after 6 Gy (p<0.05) in the C diet group but did not significantly increase in either the L-NAME, 5%G , or carrageenan groups. Tumor growth curves for the 6 Gy L-NAME and 5%G diet groups showed a corresponding statistically significant growth delay compared to 6 Gy C diet. No clear difference in bioluminescence or growth was noted in any 0 Gy cohort. CONCLUSIONS: The results support the hypothesis that radiation injury indirectly upregulates HIF1α via an iNOS dependent pathway. Inhibition of this pathway can enhance in vivo radiation-induced tumor growth delay and can be achieved via dietary supplementation with G. Thus, dietary G supplementation might have a clinical role for patients treated with radiotherapy for prostate cancer as a non-toxic means of achieving radiosensitization.
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- Oncology & Carcinogenesis
- 1112 Oncology and Carcinogenesis
- 1103 Clinical Sciences
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Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Oncology & Carcinogenesis
- 1112 Oncology and Carcinogenesis
- 1103 Clinical Sciences