Abstract
Nonmelanoma skin cancer afflicts more than one million people in the U.S. annually, highlighting the need for more effective preventive regimens. We have investigated the ability of deguelin, a plant-derived rotenoid with cancer chemopreventive activity, to inhibit UVB-induced skin carcinogenesis with the SKh-1 mouse model. Topically-applied deguelin significantly inhibited the multiplicity of UVB-induced skin tumors, indicating potential as a human skin cancer chemopreventive agent. Mechanistic studies to determine the potential of deguelin to block a number of established UVB-induced molecular events yielded negative results [including UVB-induced AP-1 DNA binding, c-fos and TNFα mRNA induction, arachidonic acid release and UVB-induced phosphorylation of mTOR (Ser2448), akt (Ser473) and erk (Thr202/Tyr204)]. These results are of interest as they contradict a major hypothesis for the mode of action of deguelin, i.e., a general down regulation of signal transduction based on inhibition of NADH dehydrogenase and depletion of ATP levels. In the current work, however, deguelin was found to activate 5′ AMP-activated kinase (AMPK), a protein that acts as a cellular energy sensor. This is the first report of a chemopreventive agent having this effect and suggests a possible role for AMPK in cancer chemoprevention.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 297-301 |
| Number of pages | 5 |
| Journal | Journal of Chemotherapy |
| Volume | 17 |
| Issue number | 3 |
| State | Published - Jun 2005 |
| Externally published | Yes |
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Keywords
- 5′ AMP-activated kinase (AMPK)
- Chemoprevention
- Deguelin
- Nonmelanoma skin cancer (NMSC)
- Ultraviolet B radiation (UVB)
ASJC Scopus subject areas
- Pharmacology (medical)
- Microbiology (medical)
Cite this
Effect of deguelin on UVB-induced skin carcinogenesis. / Gills, Joell; Kosmeder, J.; Moon, R. C.; Lantvit, D. D.; Pezzuto, J. M.
In: Journal of Chemotherapy, Vol. 17, No. 3, 06.2005, p. 297-301.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effect of deguelin on UVB-induced skin carcinogenesis
AU - Gills, Joell
AU - Kosmeder, J.
AU - Moon, R. C.
AU - Lantvit, D. D.
AU - Pezzuto, J. M.
PY - 2005/6
Y1 - 2005/6
N2 - Nonmelanoma skin cancer afflicts more than one million people in the U.S. annually, highlighting the need for more effective preventive regimens. We have investigated the ability of deguelin, a plant-derived rotenoid with cancer chemopreventive activity, to inhibit UVB-induced skin carcinogenesis with the SKh-1 mouse model. Topically-applied deguelin significantly inhibited the multiplicity of UVB-induced skin tumors, indicating potential as a human skin cancer chemopreventive agent. Mechanistic studies to determine the potential of deguelin to block a number of established UVB-induced molecular events yielded negative results [including UVB-induced AP-1 DNA binding, c-fos and TNFα mRNA induction, arachidonic acid release and UVB-induced phosphorylation of mTOR (Ser2448), akt (Ser473) and erk (Thr202/Tyr204)]. These results are of interest as they contradict a major hypothesis for the mode of action of deguelin, i.e., a general down regulation of signal transduction based on inhibition of NADH dehydrogenase and depletion of ATP levels. In the current work, however, deguelin was found to activate 5′ AMP-activated kinase (AMPK), a protein that acts as a cellular energy sensor. This is the first report of a chemopreventive agent having this effect and suggests a possible role for AMPK in cancer chemoprevention.
AB - Nonmelanoma skin cancer afflicts more than one million people in the U.S. annually, highlighting the need for more effective preventive regimens. We have investigated the ability of deguelin, a plant-derived rotenoid with cancer chemopreventive activity, to inhibit UVB-induced skin carcinogenesis with the SKh-1 mouse model. Topically-applied deguelin significantly inhibited the multiplicity of UVB-induced skin tumors, indicating potential as a human skin cancer chemopreventive agent. Mechanistic studies to determine the potential of deguelin to block a number of established UVB-induced molecular events yielded negative results [including UVB-induced AP-1 DNA binding, c-fos and TNFα mRNA induction, arachidonic acid release and UVB-induced phosphorylation of mTOR (Ser2448), akt (Ser473) and erk (Thr202/Tyr204)]. These results are of interest as they contradict a major hypothesis for the mode of action of deguelin, i.e., a general down regulation of signal transduction based on inhibition of NADH dehydrogenase and depletion of ATP levels. In the current work, however, deguelin was found to activate 5′ AMP-activated kinase (AMPK), a protein that acts as a cellular energy sensor. This is the first report of a chemopreventive agent having this effect and suggests a possible role for AMPK in cancer chemoprevention.
KW - 5′ AMP-activated kinase (AMPK)
KW - Chemoprevention
KW - Deguelin
KW - Nonmelanoma skin cancer (NMSC)
KW - Ultraviolet B radiation (UVB)
UR - http://www.scopus.com/inward/record.url?scp=22244457999&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=22244457999&partnerID=8YFLogxK
M3 - Article
C2 - 16041863
AN - SCOPUS:22244457999
VL - 17
SP - 297
EP - 301
JO - Journal of Chemotherapy
JF - Journal of Chemotherapy
SN - 1120-009X
IS - 3
ER -