Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis.
Tobacco carcinogens induce Akt activation and lung carcinogenesis. We previously demonstrated that deguelin, a natural plant product, specifically inhibits the proliferation of premalignant and malignant human bronchial epithelial cells by blocking Akt activation. To evaluate the ability of deguelin to block tobacco carcinogen-induced lung tumorigenesis, we evaluated the in vivo effects of deguelin on Akt activation and lung tumorigenesis in transgenic mice in which Akt expression was induced by tamoxifen and in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice. Deguelin suppressed Akt activation in vivo, as measured by immunohistochemistry and immunoblotting, and statistically significantly reduced NNK/BaP-induced lung tumor multiplicity, volume, and load in A/J mice, as monitored by microcomputed tomography image analysis, with no detectable toxicity. These results indicate that deguelin warrants consideration as a chemopreventive agent for early-stage lung carcinogenesis in a clinical lung cancer chemoprevention trial.
Lee
Ho-Young
HY
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. hlee@mdanderson.org
Oh
Seung-Hyun
SH
Woo
Jong K
JK
Kim
Woo-Young
WY
Van Pelt
Carolyn S
CS
Price
Roger E
RE
Cody
Dianna
D
Tran
Hai
H
Pezzuto
John M
JM
Moriarty
Robert M
RM
Hong
Waun Ki
WK
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene; D001984:Bronchial Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009602:Nitrosamines; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D012907:Smoking / Q000009:adverse effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D009602:Nitrosamines; D014028:Tobacco Smoke Pollution; D012402:Rotenone; D001564:Benzo(a)pyrene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051057:Proto-Oncogene Proteins c-akt; C107676:deguelin