Regulation of ornithine decarboxylase induction by deguelin, a natural product cancer chemopreventive agent.
Deguelin, a plant-derived rotenoid, mediates potent chemopreventive responses through transcriptional regulation of phorbol ester-induced ornithine decarboxylase (ODC) activity. To explore the mechanism of this effect, the activity of this compound was evaluated with a number of model systems. Using cultured mouse epidermal 308 cells, the steady-state levels of both 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC mRNA and c-fos were decreased by treatment with deguelin. ODC activity was also inhibited by bullatacin and various antimitotic agents (podophyllotoxin, vinblastine, and colchicine), but only deguelin and bullatacin were active as inhibitors of ODC levels in a TPA-independent c-Myc-mediated induction system using cultured BALB/c c-MycER cells. These results suggest that antimicrotubule effects, as mediated by rotenone, for example, are not responsible for inhibitory activity facilitated by deguelin. This was confirmed by use of an in vitro model of tubulin polymerization in which deguelin and a variety of other rotenoids were investigated and found to be inactive. As anticipated, however, NADH dehydrogenase was inhibited by these rotenoids. Moreover, inhibition of this enzyme correlated with a rapid depletion of ATP levels and potential to inhibit either TPA- or c-Myc-induced ODC activity. It therefore seems that deguelin-mediated interference with transient requirements for elevated energy can inhibit the induction of ODC activity and thereby yield a cancer chemopreventive response.
Gerhauser
C
C
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
Lee
S K
SK
Kosmeder
J W
JW
Moriarty
R M
RM
Hamel
E
E
Mehta
R G
RG
Moon
R C
RC
Pezzuto
J M
JM
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D051379:Mice; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011108:Polymers; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D065108:Ornithine Decarboxylase Inhibitors; D011108:Polymers; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014404:Tubulin; D000255:Adenosine Triphosphate; D009245:NADH Dehydrogenase; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate