Chemopreventive effects of zinc on prostate carcinogenesis induced by N-methyl-N-nitrosourea and testosterone in adult male Sprague-Dawley rats.
OBJECTIVE
Zinc is an important micronutrient involved in structural and regulatory functions in mammalian cells. It inhibits proliferation of both androgen-dependent and -independent prostate cancer in vitro. However, no report is available on the chemopreventive role of zinc on prostate cancer initiation in in vivo model. The main purpose of this study was to assess the chemopreventive effects of zinc on prostate carcinogenesis induced by a single dose of N-methyl-N-nitrosourea (MNU) and continuous testosterone administration in Sprague-Dawley rats.


METHODS
In this study, prostate cancer was induced in Sprague-Dawley rats using MNU+ testosterone (MNU + T). Rats were simultaneously treated with zinc (100 ppm) thrice a week. Serum and tissue activity of prostatic acid phosphatase (PAcP) was measured using biochemical analysis. Serum and tissue zinc levels were assessed by atomic absorption spectrophotometry. The ventral prostatic citrate level, phase I drug-metabolizing enzymes such as cytochrome P450, cytochrome b(5), cytochrome b(5) reductase, cytochrome C reductase, phase II enzyme like glutathione-S-transferase, lipid peroxidation, hydrogen peroxide (H(2)O(2)), and reduced glutathione were also analyzed by biochemical assays. Protein expressions of p53, proliferating cell nuclear antigen (PCNA), caspase-3, and B-cell lymphoma protein-X(L) (Bcl-X(L)) were detected by Western blot analysis. Histopathological evaluation of ventral prostate was studied using hematoxylin and eosin staining method.


RESULTS
MNU + T-treated rats showed 60, 50, and 30% of hyperplastic, dysplastic, and prostatic intraepithelial neoplastic changes, respectively, in ventral prostate, whereas MNU + T along with zinc-treated rats showed an incidence of each 10% of hyperplasia, dysplasia, and prostatic intraepithelial neoplasia in the ventral prostate. Serum zinc level and PAcP activity were significantly increased in MNU + T-treated rats, whereas these were decreased in zinc-treated rats. The ventral prostatic PAcP and glutathione-S-transferase activities, zinc, citrate, reduced glutathione levels, and protein levels of p53, caspase-3 were significantly decreased in MNU + T-treated rats, whereas increased in zinc-treated rats. Phase I drug-metabolizing enzyme activities, lipid peroxidation, H(2)O(2) levels, PCNA, and Bcl-X(L) levels were increased in MNU + T-treated rats, whereas these levels were restored to within normal limits in zinc-treated rats.


CONCLUSIONS
This study suggests that zinc may have a beneficial effect against MNU and testosterone-induced prostate carcinogenesis. Thus, it may act as a potential chemopreventive agent in targeting the prostate cancer.
Banudevi
S
S
Department of Endocrinology, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai, Tamilnadu 600113, India.
Elumalai
P
P
Arunkumar
R
R
Senthilkumar
K
K
Gunadharini
D N
DN
Sharmila
G
G
Arunakaran
J
J
D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008770:Methylnitrosourea / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D015032:Zinc / Q000494:pharmacology*; D051020:bcl-X Protein / Q000032:analysis
D016588:Anticarcinogenic Agents; C494813:Bcl2l1 protein, rat; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D013739:Testosterone; D008770:Methylnitrosourea; D000135:Acid Phosphatase; D015032:Zinc