Chemopreventive effects of the p53-modulating agents CP-31398 and Prima-1 in tobacco carcinogen-induced lung tumorigenesis in A/J mice.

Abstract

Lung cancer is the leading cause of cancer deaths worldwide. Expression of the p53 tumor suppressor protein is frequently altered in tobacco-associated lung cancers. We studied chemopreventive effects of p53-modulating agents, namely, CP-31398 and Prima-1, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung adenoma and adenocarcinoma formation in female A/J mice. Seven-week-old mice were treated with a single dose of NNK (10 µmol/mouse) by intraperitoneal injection and, 3 weeks later, were randomized to mice fed a control diet or experimental diets containing 50 or 100 ppm CP-31398 or 150 or 300 ppm Prima-1 for either 17 weeks (10 mice/group) or 34 weeks (15 mice/group) to assess the efficacy against lung adenoma and adenocarcinoma. Dietary feeding of 50 or 100 ppm CP-31398 significantly suppressed (P < .0001) lung adenocarcinoma by 64% and 73%, respectively, after 17 weeks and by 47% and 56%, respectively, after 34 weeks. Similarly, 150 or 300 ppm Prima-1 significantly suppressed (P < .0001) lung adenocarcinoma formation by 56% and 62%, respectively, after 17 weeks and 39% and 56%, respectively, after 34 weeks. Importantly, these results suggest that both p53 modulators cause a delay in the progression of adenoma to adenocarcinoma. Immunohistochemical analysis of lung tumors from mice exposed to p53-modulating agents showed a significantly reduced tumor cell proliferation and increased accumulation of wild-type p53 in the nucleus. An increase in p21- and apoptotic-positive cells was also observed in lung tumors of mice exposed to p53-modulating agents. These results support a chemopreventive role of p53-modulating agents in tobacco carcinogen-induced lung adenocarcinoma formation.

• Authors: Chinthalapally V Rao, Jagan Mohan R Patlolla, Li Qian, Yuting Zhang, Misty Brewer, Altaf Mohammed, Dhimant Desai, Shantu Amin, Stan Lightfoot, Levy Kopelovich
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 15 Issue 9 Pg. 1018-27 (Sep 2013) ISSN: 1476-5586 [Electronic] United States
• PMID: 24027427 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Cyclin-Dependent Kinase Inhibitor p21
• Nitrosamines
• Pyrimidines
• Tumor Suppressor Protein p53
• 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
• CP 31398

Topics

• Adenocarcinoma (chemically induced, drug therapy, prevention & control)
• Animals
• Anticarcinogenic Agents (therapeutic use)
• Apoptosis (drug effects)
• Aza Compounds (therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use)
• Cell Transformation, Neoplastic (drug effects)
• Chemoprevention
• Cyclin-Dependent Kinase Inhibitor p21 (biosynthesis)
• Female
• Lung Neoplasms (chemically induced, drug therapy, prevention & control)
• Mice
• Mice, Inbred A
• Nitrosamines
• Pyrimidines (therapeutic use)
• Random Allocation
• Tobacco
• Tumor Suppressor Protein p53 (drug effects)