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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA

Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA

Published on: December 19, 2019

Prevention of carcinogen and inflammation-induced dermal cancer by oral rapamycin includes reducing genetic damage

Vinh Dao¹, Srilakshmi Pandeswara², Yang Liu³

¹The 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 Prevention Research (Philadelphia, Pa.)

|March 5, 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.

Insights

Oral microencapsulated rapamycin (eRapa) prevents skin cancer by reducing DNA damage, not by inhibiting mTORC1 signaling. This novel mechanism offers a potential new strategy for cancer prevention in humans.

Area of Science:

Oncology
Molecular Biology
Dermatology

Background:

Cancer prevention is crucial and cost-effective.
Rapamycin, an mTOR inhibitor, shows promise in preventing spontaneous cancers in mice.
The efficacy of rapamycin in inflammation-driven skin carcinogenesis requires further investigation.

Purpose of the Study:

To investigate the cancer prevention efficacy of oral microencapsulated rapamycin (eRapa) in a mouse model of skin carcinogenesis.
To elucidate the underlying molecular mechanisms of eRapa's cancer prevention effects.
To explore the potential of eRapa as a broad-spectrum cancer prevention agent.

Main Methods:

Mice were exposed to dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce skin carcinogenesis.
Oral microencapsulated rapamycin (eRapa) was administered before or after carcinogen exposure.
Tumor latency, prevalence, and malignant transformation were assessed.
mTORC1 signaling, inflammatory markers, stem cell populations, and DNA damage were analyzed in skin and papillomas.
In vitro studies with fibroblasts were conducted to assess DNA damage reduction.

Main Results:

eRapa administration before DMBA/TPA significantly delayed tumor onset, reduced papilloma formation, and prevented squamous cell carcinoma.
eRapa did not inhibit mTORC1 signaling or key proinflammatory factors in the skin.
eRapa reduced DMBA/TPA-induced DNA damage and the specific hras codon 61 mutation.
The cancer prevention and DNA damage reduction effects were lost when eRapa was given after carcinogen exposure.
eRapa achieved picomolar concentrations in the skin and reduced DNA damage in vitro.

Conclusions:

Oral microencapsulated rapamycin (eRapa) effectively prevents skin cancer in a chemically induced mouse model.
DNA damage reduction is identified as a novel mechanism for rapamycin-mediated cancer prevention, independent of mTORC1 inhibition.
These findings support the potential use of eRapa as a cancer prevention strategy for specific human populations.

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