Abstract
Activation of peroxisome proliferator-activated receptor (PPAR) α disrupts growth-related activities in a variety of human cancers. This study was designed to determine whether fenofibrate, a PPARα agonist, can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced proliferative lesions in the lung of obese hyperlipidemic mice. Male Tsumura Suzuki Obese Diabetic mice were subcutaneously injected with 4-NQO to induce lung proliferative lesions, including adenocarcinomas. They were then fed a diet containing 0.01% or 0.05% fenofibrate for 29 weeks, starting 1 week after 4-NQO administration. At week 30, the incidence and multiplicity (number of lesions/mouse) of pulmonary proliferative lesions were lower in mice treated with 4-NQO and both doses of fenofibrate compared with those in mice treated with 4-NQO alone. The incidence and multiplicity of lesions were significantly lower in mice treated with 4-NQO and 0.05% fenofibrate compared with those in mice treated with 4-NQO alone (p < 0.05). Both doses of fenofibrate significantly reduced the proliferative activity of the lesions in 4-NQO-treated mice (p < 0.05). Fenofibrate also significantly reduced the serum insulin and insulin-like growth factor (IGF)-1 levels, and decreased the immunohistochemical expression of IGF-1 receptor (IGF-1R), phosphorylated Akt, and phosphorylated Erk1/2 in lung adenocarcinomas. Our results indicate that fenofibrate can prevent the development of 4-NQO-induced proliferative lesions in the lung by modulating the insulin-IGF axis.
Highlights
Despite advances in the medical treatment of lung cancer, it is still a leading cause of cancer-related death in men and women in the United States and men in Japan [1,2]
Because the effects of fenofibrate on lung carcinogenesis have not been studied, the present study examined whether dietary fenofibrate can suppress 4-nitroquinoline 1-oxide (4-NQO)-induced lung tumorigenesis in male Tsumura Suzuki Obese Diabetic (TSOD) mice
We showed that dietary administration of fenofibrate, a PPARα ligand, inhibited 4-NQO-induced pulmonary proliferative lesions in male TSOD obese hyperlipidemic mice
Summary
Despite advances in the medical treatment of lung cancer, it is still a leading cause of cancer-related death in men and women in the United States and men in Japan [1,2]. Smoking is the major cause of lung cancer. A number of molecular targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and an inhibitor of echinoderm microtubule-associated protein-like 4-anaplastic lymphoma receptor tyrosine kinase (EML4-ALK), have been developed for the treatment of non-small cell lung cancer. Despite the success of genotype-directed therapies in EGFR-mutant and ALK-positive patients, resistance necessarily develops. The median progression free survival after treatment with EGFR or ALK inhibitors in target populations is generally less than 1 year [3]. Prevention is the most effective tools of decreasing lung cancer development [4]
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