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Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage.
- Source :
-
Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2015 May; Vol. 8 (5), pp. 400-9. Date of Electronic Publication: 2015 Mar 03. - Publication Year :
- 2015
-
Abstract
- Cancer prevention is a cost-effective alternative to treatment. In mice, the mTOR inhibitor rapamycin prevents distinct spontaneous, noninflammatory cancers, making it a candidate broad-spectrum cancer prevention agent. We now show that oral microencapsulated rapamycin (eRapa) prevents skin cancer in dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) carcinogen-induced, inflammation-driven carcinogenesis. eRapa given before DMBA/TPA exposure significantly increased tumor latency, reduced papilloma prevalence and numbers, and completely inhibited malignant degeneration into squamous cell carcinoma. Rapamycin is primarily an mTORC1-specific inhibitor, but eRapa did not reduce mTORC1 signaling in skin or papillomas, and did not reduce important proinflammatory factors in this model, including p-Stat3, IL17A, IL23, IL12, IL1β, IL6, or TNFα. In support of lack of mTORC1 inhibition, eRapa did not reduce numbers or proliferation of CD45(-)CD34(+)CD49f(mid) skin cancer initiating stem cells in vivo and marginally reduced epidermal hyperplasia. Interestingly, eRapa reduced DMBA/TPA-induced skin DNA damage and the hras codon 61 mutation that specifically drives carcinogenesis in this model, suggesting reduction of DNA damage as a cancer prevention mechanism. In support, cancer prevention and DNA damage reduction effects were lost when eRapa was given after DMBA-induced DNA damage in vivo. eRapa afforded picomolar concentrations of rapamycin in skin of DMBA/TPA-exposed mice, concentrations that also reduced DMBA-induced DNA damage in mouse and human fibroblasts in vitro. Thus, we have identified DNA damage reduction as a novel mechanism by which rapamycin can prevent cancer, which could lay the foundation for its use as a cancer prevention agent in selected human populations.<br /> (©2015 American Association for Cancer Research.)
- Subjects :
- 3T3 Cells
9,10-Dimethyl-1,2-benzanthracene
Administration, Oral
Animals
Carcinogenesis chemically induced
Carcinogenesis genetics
Cells, Cultured
Chemoprevention
Down-Regulation drug effects
Down-Regulation genetics
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Skin Neoplasms chemically induced
Skin Neoplasms genetics
Carcinogenesis drug effects
Carcinogens
DNA Damage drug effects
Inflammation
Sirolimus administration & dosage
Skin Neoplasms etiology
Skin Neoplasms prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1940-6215
- Volume :
- 8
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer prevention research (Philadelphia, Pa.)
- Publication Type :
- Academic Journal
- Accession number :
- 25736275
- Full Text :
- https://doi.org/10.1158/1940-6207.CAPR-14-0313-T