Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice Nagaiya Ravichandran, Gopalakrishnan Suresh, Balasubramanian Ramesh, Ganesan Vijaiyan Siva ⇑ Department of Biotechnology, University of Madras, Guindy Campus, Chennai - 600 025, Tamilnadu, India article info Article history: Received 6 October 2010 Accepted 4 February 2011 Available online xxxx Keywords: Lung cancer Fisetin LPO PCNA abstract Lung cancer is the foremost cause of cancer mortality and is a growing economic burden worldwide. Fise- tin (3,7,3 0 ,4 0 -tetrahydroxyflavone), a naturally occurring flavonoid is found in vegetables and fruits pos- sesses anti-oxidative, anti-inflammatory and anti-proliferative effects in a wide variety of cancer. In the present study it is hypothesized that fisetin may provide chemopreventive as well as chemotherapeutic effects against experimental lung carcinogenesis. The present study was designed to investigate whether fisetin confers anti-cancer action against benzo(a)pyrene [B(a)P] induced lung carcinogenesis. Treatment with fisetin significantly reduced the degree of histological lesions, restored the levels of lipid peroxida- tion (LPO), enzymic and non-enzymic anti-oxidants in B(a)P-induced mice. Anti-proliferative efficacy of fisetin was assessed by immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) in B(a)P induced mice showed increased PCNA expression which is restored upon fisetin administration. Together, our results depicts that fisetin can be used as chemopreventive agent against lung cancer. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Lung cancer is by far the leading cause of cancer-related deaths in the developing countries. It was estimated that 1.4 million new cases would be diagnosed and approximately 1.2 million deaths every year. There are two major types of lung cancer: small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). Large cell lung carcinoma has the worst prognosis of all NSCLCs (Garcia-Yuste et al., 2008). Carcinogens from cigarette smoke form the link between nicotine addiction and lung cancer, contributing to a tenfold increase in risk in long-term smokers compared with non-smokers (Perera et al., 2008). Tobacco contents of smoke, the polycyclic aromatic hydrocarbons (PAHs) such as B(a)P, that play a major role in induction of lung carcinogenesis (Hecht et al., 2002). B(a)P is metabolized to (±)-B(a)P-r-7,t-8-dihydrodiol-t-9,10-epox- ide (BPDE), the ultimate carcinogen. BPDE isomers then bind to the hexocyclic nitrogen of deoxyguanosine in DNA via trans-addi- tion of the C-10 position in the epoxide molecule. This adduct might also cause activation of proto-oncogenes (Sticha et al., 2000). Superoxide and hydroxyl radicals along with hydrogen peroxide (H 2 O 2 ) are collectively called as reactive oxygen species (ROS). The sources of generation of ROS in cells are various metabolic reac- tions with the incomplete reduction of oxygen in mitochondrial electron transport chain during respiration (Halliwell and Gutter- idge, 2001). Superoxide radicals in turn generate hydroxyl radicals by reacting with H 2 O 2 in the presence of free iron by classical fen- ton reaction (Turrens et al., 1985). Thus generated ROS can drive the cell to a pro-oxidant state, referred as oxidative stress, affects biological molecules including membrane lipids (Halliwell and Gutteridge, 2001). The lung is exposed to higher levels of oxygen than most other tissues. The intensity of ROS in the lung is in- creased by cigarette smoke, inflammation, pollutants, chemicals and carcinogens (Cugell and Kamp, 2004). Accumulating evidence suggests that these free radicals and electrophile mediated oxida- tive stress plays an important role in all stages of chemical carcino- genesis and tumorigenesis (Sun, 1990). Chemopreventive agents have the potential to reduce the linger- ing lung cancer risk by rendering protection against the promotion and progression of carcinogenesis and hence chemoprevention may be considered for control of the lung cancer epidemic. Several re- ports suggest that phenolic compounds also act as chemopreven- tive agents by counteracting carcinogen-induced oxidative stress (Tanaka et al., 1998; Ashokkumar and Sudhandiran, 2009). Flavo- noids are low molecular weight compounds rich in seeds, citrus fruits, red wine, tea and olive oil. Flavonoids have diverse biological effects including anti-oxidant, anti-platelet, anti-thrombotic, cyto- protective, anti-allergic, anti-viral, anti-carcinogenic activities and anti-inflammatory activities (Higa et al., 2003). Fisetin (3,7,3,4-tet- rahydroxyflavone), a naturally occurring flavonoid commonly found in the smoke tree (Cotinus coggygria), is also found in fruits and vegetables such as strawberry, apple, persimmon, grape, onion and cucumber (Arai et al., 2000). It exerts a wide variety of activi- 0278-6915/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.fct.2011.02.005 ⇑ Corresponding author. Tel.: +91 044 22202743. E-mail address: gvsbio@gmail.com (G. Vijaiyan Siva). Food and Chemical Toxicology xxx (2011) xxx–xxx Contents lists available at ScienceDirect Food and Chemical Toxicology journal homepage: www.elsevier.com/locate/foodchemtox Please cite this article in press as: Ravichandran, N., et al. Fisetin, a novel flavonol attenuates benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Food Chem. Toxicol. (2011), doi:10.1016/j.fct.2011.02.005