An investigation of the effects of vitamin E succinate (VES) on human prostate LNCaP tumor growth and gene expression in BALB/c nude mice fed high-fat diets
Prostate cancer is the most diagnosed form of noncutaneous malignancy and the second leading cause of cancer death among men in the United States. The primary treatment modalities are not effective for some forms of the disease. Identification of alternate approaches such as the chemoprotective agent α-tocopheryl succinate (α-TOS) has become attractive. We studied the effects of α-TOS treatment on the growth and gene expression of human prostate LNCaP tumor cells in BALB/c nu/nu male mice (9 weeks old, n = 48) fed 20% fat (SBO or CSO) diets. Mice received subcutaneous inoculations of LNCaP tumor cells in Matrigel matrix and were randomly divided into four groups (20%-SBO, 20%-SBO+α-TOS, 20%-CSO, and 20%-CSO+α-TOS, n=12/group). On day 21 after the inoculation of LNCaP cells, groups 20%-SBO+α-TOS and 20%-CSO+α-TOS received intraperitoneal (ip) injection of α-TOS (100 mg/kg body weight) in sesame oil three times a week and groups 20%-SBO and 20%-CSO received sesame oil vehicle three times a week. At day 56 mice were sacrificed, livers and tumors were harvested, weighed and snap frozen in liquid nitrogen or stored in RNA later for hepatic tocopherol analysis by high performance liquid chromatography (HPLC) and real-time polymerase chain reaction (RT-qPCR), respectively. Quantitative comparisons of mRNA relative expressions of target genes were performed using the comparative 2-ΔΔC(t) method. Combination of the 20%-CSO diet with α-TOS treatment resulted in modest reduction of mRNA expressions of both PSA and AR, and a more pronounced reductions of mRNA expressions in VEGF-total, VEGF-165, IGF-1B and TGF-β1 genes. The use of 20%-CSO diet with vehicle-control also led to reduction in mRNA expressions of the target genes. Results from HPLC analysis of liver samples show that ip administration of α-TOS in our mouse model greatly increased the α-TOH hepatic pool and led to α-TOS storage in the liver. Taken together, these results indicate that both 20%-CSO diet and α-TOS treatment individually and in combination down regulated the studied genes and impacted the bioavailability of α-TOH in the body suggesting the relevance of these bioactive compounds as adjuvant chemotherapeutic agents in the treatment of prostate cancer.