Zinc supplementation suppresses 4-nitroquinoline 1-oxide-induced rat oral carcinogenesis.
Dietary zinc (Zn) deficiency is implicated in the pathogenesis of human oral-esophageal cancers. In rats, Zn deficiency causes increased cell proliferation and cyclooxygenase-2 (COX-2) overexpression and enhances oral carcinogenesis by 4-nitroquinoline 1-oxide (NQO). Zn replenishment reverses all these effects. We questioned whether Zn has antitumor efficacy in a Zn-sufficient animal by investigating in Zn-sufficient rats (i) the efficacy of Zn supplementation on the progression of tongue squamous cell carcinogenesis induced by drinking water exposure to high (20-30 p.p.m.) and low (10 p.p.m.) doses of NQO and (ii) the modulating effects of Zn supplementation on biomarker expression in tongue lesions by immunohistochemistry. In rats exposed to high doses of NQO, Zn supplementation significantly reduced the incidence of papillomas from 100 to 64.7% (P=0.018) and invasive carcinomas from 93.8 to 52.9% (P=0.017). In rats exposed to low doses of NQO, where only minimally invasive carcinomas developed, Zn supplementation significantly reduced tumor multiplicity, incidence of tumors (1-2 mm), hyperplasia, dysplasia, papillomas and progression to carcinoma. Immunohistochemical analysis of carcinomas showed that Zn supplementation caused a shift to a less proliferative/aggressive cancer phenotype by reducing cell proliferation, stimulating apoptosis and decreasing expression of the key tumor markers cyclin D1, p53 and COX-2. Additionally, Zn supplementation significantly reduced cell proliferation in non-lesional tongue squamous epithelia, thereby suppressing tumor development. Together, the results demonstrate that Zn supplementation has chemopreventive efficacy against oral carcinogenesis in nutritionally complete animals. Our data suggest that Zn supplementation may be efficacious in the chemoprevention of human oral cancer.
Department of Pharmacology and Experimental Therapeutics, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Louise.Fong@Jefferson.edu
Louise Y Y
LY
Fong
Yubao
Y
Jiang
Maysoon L
ML
Rawahneh
Karl J
KJ
Smalley
Carlo M
CM
Croce
John L
JL
Farber
Kay
K
Huebner
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D049109:Cell Proliferation; D019587:Dietary Supplements; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015032:Zinc / Q000008:administration & dosage* / Q000097:blood
D015112:4-Nitroquinoline-1-oxide; D015032:Zinc
J Natl Cancer Inst. 1996 Apr 17;88(8):519-29
8606380
Trends Immunol. 2007 Jan;28(1):1-4
17126599
Tokai J Exp Clin Med. 1996 Oct;21(3):139-45
9239817
Odontol Revy. 1973;24(1):39-48
4514062
Cancer Res. 1995 Feb 15;55(4):949-56
7850812
Laryngoscope. 2009 Jul;119(7):1348-52
19402154
Cancer Sci. 2003 Apr;94(4):365-71
12824906
Gastroenterology. 2009 Mar;136(3):953-66
19111725
J Natl Cancer Inst. 2001 Oct 17;93(20):1525-33
11604475
Carcinogenesis. 2011 Mar;32(3):351-8
21097531
JAMA. 1978 Nov 10;240(20):2166-8
359844
Carcinogenesis. 1998 Sep;19(9):1591-6
9771929
Cancer. 1995 Aug 15;76(4):541-9
8625145
J Natl Cancer Inst. 1981 Aug;67(2):243-51
6943364
Int J Cancer. 2008 Mar 1;122(5):978-89
17985342
Ann Oncol. 2004 Sep;15(9):1319-29
15319236
J Am Coll Nutr. 1997 Oct;16(5):418-22
9322189
Int J Cancer. 2011 Jul 15;129(2):331-45
20857495
Cancer Res. 1980 Aug;40(8 Pt 1):2633-44
6992989
Trends Biochem Sci. 1995 May;20(5):187-90
7610482
Cancer Lett. 1989 Dec;48(3):177-82
2514039
Cancer Res. 1993 Feb 15;53(4):772-6
8428357
Arch Ophthalmol. 2004 May;122(5):716-26
15136320
Cancer Epidemiol Biomarkers Prev. 2001 Mar;10(3):191-9
11303587
Carcinogenesis. 2009 Jul;30(7):1073-81
19468060
Cancer Res. 1994 Sep 15;54(18):4855-78
8069852
Crit Rev Toxicol. 1993;23(1):77-109
8097093
Oncogene. 2011 Jan 6;30(1):117-26
20818437
Cancer Res. 1999 Jan 1;59(1):198-204
9892207
Cancer. 1953 Sep;6(5):963-8
13094644
Toxicol Lett. 2007 Jun 15;171(1-2):10-8
17590543
Virchows Arch. 2002 Jun;440(6):594-7
12070598
Cell. 2000 Jan 7;100(1):57-70
10647931
J Exp Clin Cancer Res. 2009 Jun 17;28:84
19534805
J Natl Cancer Inst. 2005 Jan 5;97(1):40-50
15632379
Cancer Prev Res (Phila). 2010 Jan;3(1):73-81
20051374
Physiol Rev. 1993 Jan;73(1):79-118
8419966
Eur J Cancer B Oral Oncol. 1995 Jan;31B(1):3-15
7627084
Science. 1993 Aug 6;261(5122):715-25
8342038
Am J Clin Nutr. 2010 Jun;91(6):1634-41
20427734
Mund Kiefer Gesichtschir. 1998 Nov;2(6):320-5
9881002
Nutr Cancer. 2009;61(6):879-87
20155630
Oral Dis. 2000 Mar;6(2):75-84
10702783
Cancer Res. 2001 Feb 15;61(4):1451-6
11245450
Int J Radiat Oncol Biol Phys. 2008 Feb 1;70(2):368-73
17980503
Histol Histopathol. 2003 Jan;18(1):39-48
12507282
J Osaka Dent Univ. 1996 Dec;30(1-2):29-35
9485768
J Natl Cancer Inst. 2005 Feb 16;97(4):301-6
15713965
Int J Cancer. 2001 Oct 15;94(2):153-6
11668491