Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage.
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.
The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas. Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
Vinh
V
Dao
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
Srilakshmi
S
Pandeswara
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas. Xiangya School of Medicine, Central South University, Changsha, Hunan, P.R. China.
Yang
Y
Liu
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
Vincent
V
Hurez
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Sherry
S
Dodds
The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas.
Danielle
D
Callaway
Department of Medicine, University of Texas Health Science Center, San Antonio, Texas.
Aijie
A
Liu
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Paul
P
Hasty
Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, Texas.
Zelton D
ZD
Sharp
The Graduate School of Biomedical Sciences, University of Texas Health Science Center, San Antonio, Texas. Department of Medicine, University of Texas Health Science Center, San Antonio, Texas. Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas. curielt@uthscsa.edu.
Tyler J
TJ
Curiel
D016475:3T3 Cells; D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects* / Q000235:genetics; D002273:Carcinogens; D002478:Cells, Cultured; D018890:Chemoprevention; D004249:DNA Damage / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020123:Sirolimus / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control*
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D020123:Sirolimus