Co-treatment with atorvastatin and bevacizumab improved antitumor efficacy and biochemical status in lung cancer in vivo

Abstract

Lung cancer is one of the most common cancers worldwide. Atorvastatin (ATOR), an anti-cholesterol drug, was shown recently to employ a probable effect against lung cancer. Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody antagonist, is a known lung cancer remedy. This study aimed to address the effects of co-treatment of ATOR and bevacizumab against mouse lung cancer. Male mice were divided into 5 groups. Group 1 (G1), was used as a normal control. Groups 2-5 were administered with urethane (Ure) (1mg/g) and butylated hydroxy-toluene (BHT) (150 or 200 mg/kg) for lung cancer initiation and promotion respectively. G2 was a carcinogen-only control. G3 was post-treated with 10 mg/kg ATOR. G4 was treated with 5 mg/kg bevacizumab. G5 was co-treated with ATOR and bevacizumab. Co-treatment with ATOR and bevacizumab significantly decreased the tumor incidences, multiplicities, and sizes as compared with each treatment alone. Also, the combination treatment has reduced the immunohistochemical proliferating cell nuclear antigen labeling indexes (PCNA LI%) in lung parenchyma and tumors. Further, the treatment with ATOR/bevacizumab has significantly caused a G0/1 cell cycle arrest, induced apoptosis in cells and tumors, and ameliorated the antioxidative stress parameters in lung tissues. Furthermore, co-treatment with ATOR/bevacizumab has shown upregulation of mitogen-activated protein kinase (MAPK) and downregulation of Heme oxygenase (HMOX1), nitric oxide synthase 2 (NOS2), and VEGF genes. Collectively, ATOR co-treatment has significantly improved bevacizumab's efficacy against lung cancer in mice, through induction of apoptosis, inhibition of cell proliferation, and causing G0/1 cell cycle arrest, without adverse side effects.