Elsevier

Biomedicine & Pharmacotherapy

Volume 82, August 2016, Pages 568-577
Biomedicine & Pharmacotherapy

Antioxidant and antitumor efficacy of Luteolin, a dietary flavone on benzo(a)pyrene-induced experimental lung carcinogenesis

https://doi.org/10.1016/j.biopha.2016.05.042 Get rights and content

Highlights

  • Chemopreventive effect of luteolin, a dietary flavone, is evaluated against B(a)P induced lung cancer.

  • Luteolin restored the tumor markers enzymes, lipid peroxidation and antioxidant levels.

  • Luteolin protected the histoarchitecture of lungs in B(a)P intoxicated mice.

  • Luteolin treatment downregulated the PCNA, CYP1A1 and NF-κB expression.

Abstract

The present study is designed to assess the antioxidant and antitumor potential of luteolin against benzo(a)pyrene [B(a)P]-induced lung carcinogenesis in Swiss albino mice. Here, we reported that oral administration of B(a)P (50 mg/kg body weight) to mice resulted in raised lipid peroxides (LPO), lung specific tumor markers such as carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) with concomitant decrease in the levels of both enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione-s-transferase (GST), and non-enzymatic antioxidants such as reduced glutathione (GSH), vitamin E and vitamin C. Luteolin treatment (15 mg/kg body weight, p.o) significantly counteracted all these alterations and maintained cellular normalcy. Moreover, assessment of protein expression levels by western blot analysis revealed that luteolin treatment effectively negates B(a)P-induced upregulated expression of proliferating cell nuclear antigen (PCNA), cytochrome P450 1A1 (CYP1A1) and nuclear factor-kappa B (NF-κB). Furthermore, histopathology of lung tissue and immunohistochemistry of CYP1A1 were carried out to substantiate the anti- lung cancer effect of luteolin. Overall, these findings confirm the chemopreventive potential of luteolin against B(a)P induced lung carcinogenesis.

Introduction

Lung cancer is a major cause of morbidity and mortality worldwide in both men and women, accounting for 20% of all cancers [1]. Benzo(a)pyrene, a prototype lung carcinogen of poly aromatic hydrocarbon class, is known to induce enormous amounts of free radicals which results in oxidative stress that plays a crucial role in B(a)P-induced lung carcinogenesis [2]. The persisting grim of lung cancer mortality figures urge to discover novel approaches to control this deadly disease. In the recent years, dietary phytochemicals have fascinated the attention of researchers due to their promise of being powerful antioxidants that can protect human beings from free radical induced toxic effects. A large number epidemiological and experimental studies have convincingly proved that high dietary intake of fruits and vegetables rich in antioxidants have presented favourable effects in the chemoprevention of a multitude of diseases, including lung cancer [2], [3].

Chemoprevention refers to the use of natural, dietary or synthetic compounds to prevent, reverse, or delay the development of cancer [4]. A number of effective chemopreventive measures have been introduced considerably to reduce both the incidence and mortality from lung cancer; among them use of dietary agents have gained immense interest for development as chemopreventive agents to treat lung cancer owing to their ubiquitous nature, inexpensiveness and broad safety window [2], [4], [5]. Luteolin is one such compound with promising role in cancer. Luteolin, 3′,4′,5,7-tetrahydroxyflavone (Fig. 1), a dietary phytochemical, belongs to a group of naturally occurring compounds called flavones, a type of flavonoids that are widely present in fruits and vegetables such as apples, celery, peppers, parsley, onion leaves, broccoli, carrots and cabbages [6]. Luteolin, possess many beneficial properties including antioxidant, anti-inflammatory, cardio protective, anti-diabetic and anti-proliferative [6], [7]. Luteolin has recently reported to show protective properties against several experimental carcinogenesis [8]. These studies have demonstrated that luteolin has promising potential as a chemopreventive agent and is worthy of further study. Therefore, the primary objective of the present study is to assess the antioxidant and antitumor efficacy of luteolin in B(a)P induced lung carcinogenesis in Swiss albino mice and to explore the possible mechanisms.

Section snippets

Chemicals

Benzo(a)pyrene (purity, ∼96%) and β-actin antibody were purchased from Sigma Aldrich (St Louis, MO, USA). Luteolin was purchased from TCI Company (Tokyo, Japan). The primary and secondary antibodies used in our experiment were procured from Santa Cruz Biotechnology (Santa Cruz, CA, USA). All other chemicals and solvents used were of the highest analytical grade procured from commercial sources.

Animals

Healthy male Swiss albino mice, 6–8 weeks old, weighing 18–22 g were used in the study. Mice were

General observations

Table 1 shows the effect of benzo(a)pyrene and luteolin on body weight, lung weight and tumor incidence in control and experimental group of animals. In our study, significant (P < 0.05) increase in the lung weight and tumor incidence with concomitant decrease in body weight were observed in B(a)P induced lung cancer-bearing animals (Group III). Luteolin treatment markedly (p < 0.05) increased body weight and reduced lung weight and tumor incidence in both pre-treated (Group IV) and post-treated

Discussion

Lung cancer is currently a leading cause of death worldwide and chemoprevention considered as a realistic approach [19]. Experimental evidences have suggested that dietary intake of flavonoids rich in antioxidants reduce further risk of developing lung cancer [3], [20]. Luteolin, a dietary flavone type flavonoid available in many fruits and vegetables reported to show antioxidant properties both in in vitro and in vivo models [7]. Luteolin has been extensively studied as chemopreventive agent

Conclusion

In conclusion, the present study reports for the first time that luteolin, the dietary flavone, prevents B(a)P-induced lung carcinogenesis in Swiss albino mice through its potent free radical scavenging, antioxidant, anti-initiating, anti-inflammatory and anti-proliferative effects. Luteolin effect is more pronounced when used as a chemopreventive agent rather than chemotherapeutic agent against B(a)P induced lung carcinogenesis. Hence, luteolin may develop as a chemopreventive drug to reduce

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

We would like to thank National Institute of Pharmaceutical Education and Research-Guwahati, under the aegis of Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for financial support. All authors are extremely thankful to Institutional Biotech Hub of NIPER-Guwahati for providing the laboratory facilities.

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