Carcinogenesis Advance Access originally published online on September 30, 2009
Carcinogenesis 2009 30(11):1949-1956; doi:10.1093/carcin/bgp229
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Curcumin inhibits COPD-like airway inflammation and lung cancer progression in mice
1 Department of Pulmonary Medicine
2 Department of Thoracic Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
3 Tecnológico de Monterrey School of Medicine, Monterrey, Nuevo León 64710, Mexico
4 Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
5 Institute of Biosciences and Technology, Center for Inflammation and Infection, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA
* To whom correspondence should be addressed. Tel: +1 713 563 0423; Fax: +1 713 563 0411; Email: smoghadd{at}mdanderson.org
Recent studies have demonstrated that K-ras mutations in lung epithelial cells elicit inflammation that promotes carcinogenesis in mice (intrinsic inflammation). The finding that patients with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have an increased risk of lung cancer after controlling for smoking suggests a further link between lung cancer and extrinsic inflammation. Besides exposure to cigarette smoke, it is thought that airway inflammation in COPD is caused by bacterial colonization, particularly with non-typeable Hemophilus influenzae (NTHi). Previously, we have shown that NTHi-induced COPD-like airway inflammation promotes lung cancer in an airway conditional K-ras-induced mouse model. To further test the role of inflammation in cancer promotion, we administered the natural anti-inflammatory agent, curcumin, 1% in diet before and during weekly NTHi exposure. This significantly reduced the number of visible lung tumors in the absence of NTHi exposure by 85% and in the presence of NTHi exposures by 53%. Mechanistically, curcumin markedly suppressed NTHi-induced increased levels of the neutrophil chemoattractant keratinocyte-derived chemokine by 80% and neutrophils by 87% in bronchoalveolar lavage fluid. In vitro studies of murine K-ras-induced lung adenocarcinoma cell lines (LKR-10 and LKR-13) indicated direct anti-tumoral effects of curcumin by reducing cell viability, colony formation and inducing apoptosis. We conclude that curcumin suppresses the progression of K-ras-induced lung cancer in mice by inhibiting intrinsic and extrinsic inflammation and by direct anti-tumoral effects. These findings suggest that curcumin could be used to protract the premalignant phase and inhibit lung cancer progression in high-risk COPD patients.
Abbreviations: BALF, bronchoalveolar lavage fluid; CC-LR, CCSPCre/LSL-K-rasG12Dmice; CCSP, Clara cell secretory protein; COPD, chronic obstructive pulmonary disease; IL, interleukin; KC, keratinocyte-derived chemokine; NTHi, non-typeable Hemophilus influenzae; PBS, phosphate buffered saline; WT, wild type
Received May 8, 2009; revised July 29, 2009; accepted September 18, 2009.