Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: Chemoprevention by budesonide and N-acetylcysteine

doi:10.1073/pnas.0601412103

Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: Chemoprevention by budesonide and N-acetylcysteine

*Department of Health Sciences, University of Genoa, Via A. Pastore 1, I-16132 Genoa, Italy;
^†National Center of Oncology, Sofia 1756, Bulgaria;
^‡National Cancer Institute, Rockville, MD 20898; and
^§Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210

Edited by Webster K. Cavenee, University of California at San Diego School of Medicine, La Jolla, CA, and approved March 29, 2006 (received for review February 20, 2006)

Abstract

The FHIT gene has many hallmarks of a tumor-suppressor gene and is involved in a large variety of cancers. We treated A/J mice and (C57BL/6J × 129/SvJ)F₁ (B6/129 F₁) mice, either wild-type or FHIT ^+/−, with multiple doses of benzo[a]pyrene (B[a]P) by gavage. B[a]P caused a time-related increase of micronuclei in peripheral blood erythrocytes. Both A/J and B6/129 F₁ mice, irrespective of their FHIT status, were sensitive to induction of forestomach tumors, whereas B[a]P induced glandular stomach hyperplasia and a high multiplicity of lung tumors in A/J mice only. Preneoplastic lesions of the uterus were more frequent in FHIT ^+/− mice. B6/129 F₁ mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which were greatly accelerated either by FHIT heterozygosity or by B[a]P treatment, thus suggesting that FHIT plays a role in the pathogenesis of alopecia areata. The oral administration of either budesonide or N-acetyl-l-cysteine (NAC) inhibited the occurrence of this inflammatory skin disease. In addition, these agents prevented B[a]P-induced glandular stomach hyperplasia and decreased the size of both forestomach tumors and lung tumors in A/J mice. Budesonide also attenuated lung tumor multiplicity. In B6/129 F₁ mice, NAC significantly decreased the proliferating cell nuclear antigen in lung tumors. Both budesonide and NAC inhibited B[a]P-induced forestomach tumors and preneoplastic lesions of the respiratory tract in B6/129 F₁ mice. In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC.

Footnotes

^¶To whom correspondence should be addressed. E-mail: sdf{at}unige.it
Author contributions: R.B., R.A.L., and S.D.F. designed research; R.B., F.D., G.G., A.I., B.D.M., and N.Z. performed research; F.D. and S.D.F. analyzed data; and C.M.C. and S.D.F. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

B[a]P,

benzo[a]pyrene;

Fhit,

fragile histidine triad;

MN,

micronucleated;

NAC,

N-acetyl-l-cysteine;

NCE,

normochromatic erythrocytes;

PCNA,

proliferating cell nuclear antigen.