Carcinogenesis Advance Access originally published online on April 9, 2009
Carcinogenesis 2009 30(6):1016-1023; doi:10.1093/carcin/bgp082
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Lung tumor promotion by curcumin
1 Department of Cancer Biology
2 Section on Comparative Medicine, Department of Pathology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
3 Department of Medicine, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY 10467, USA
4 Department of Biostatistical Sciences
5 Department of Biochemistry and Molecular Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
* To whom correspondence should be addressed. Department of Cancer Biology, 1 Medical Center Boulevard, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. Tel: +1 336 716 0795; Fax: +1 336 716 0255; Email: msmiller{at}wfubmc.edu
Curcumin exhibits anti-inflammatory and antitumor activity and is being tested in clinical trials as a chemopreventive agent for colon cancer. Curcumin's chemopreventive activity was tested in a transgenic mouse model of lung cancer that expresses the human Ki-rasG12C allele in a doxycycline (DOX) inducible and lung-specific manner. The effects of curcumin were compared with the lung tumor promoter, butylated hydroxytoluene (BHT), and the lung cancer chemopreventive agent, sulindac. Treatment of DOX-induced mice with dietary curcumin increased tumor multiplicity (36.3 ± 0.9 versus 24.3 ± 0.2) and progression to later stage lesions, results which were similar to animals that were co-treated with DOX/BHT. Microscopic examination showed that the percentage of lung lesions that were adenomas and adenocarcinomas increased to 66% in DOX/BHT, 66% in DOX/curcumin and 49% in DOX/BHT/curcumin-treated groups relative to DOX only treated mice (19%). Immunohistochemical analysis also showed increased evidence of inflammation in DOX/BHT, DOX/curcumin and DOX/BHT/curcumin mice relative to DOX only treated mice. In contrast, co-treatment of DOX/BHT mice with 80 p.p.m. of sulindac inhibited the progression of lung lesions and reduced the inflammation. Lung tissue from DOX/curcumin-treated mice demonstrated a significant increase (33%; P = 0.01) in oxidative damage, as assessed by the levels of carbonyl protein formation, relative to DOX-treated control mice after 1 week on the curcumin diet. These results suggest that curcumin may exhibit organ-specific effects to enhance reactive oxygen species formation in the damaged lung epithelium of smokers and ex-smokers. Ongoing clinical trials thus may need to exclude smokers and ex-smokers in chemopreventive trials of curcumin.
Abbreviations: AC, adenocarcinomas; AD, adenoma; BHT, butylated hydroxytoluene; CCSP, Clara cell secretory protein; COX-2, cycloxygenase-2; DOX, doxycycline; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IHC, immunohistochemistry; NF-
β, nuclear factor β; RT–PCR, reverse transcription-polymerase chain reaction; rtTA, reverse tetracycline trans-activator
Received September 12, 2008; revised March 27, 2009; accepted March 27, 2009.