Survival Benefit of Statin with Anti-Angiogenesis Efficacy in Lung Cancer-Associated Pleural Fluid through FXR Modulation

Abstract

Lung cancer-related pleural fluid (LCPF) presents as a common complication with limited treatment. Beyond its function in lipid digestion, bile acid was identified as a potent carcinogen to stimulate tumor proliferation. Previous research indicated a correlation between serum bile acid levels and the risk of developing several gastrointestinal cancers. Our study identified elevated bile acid levels in LCPF and increased farnesoid X receptor (FXR) expression as bile acid nuclear receptors in pleural microvessels of lung adenocarcinoma. Additionally, LCPF stimulated the expression of proteins involved in bile acid synthesis and cholesterol metabolism in HUVECs including CYP7A1, StAR, HMGCR, and SREBP2. LCPF-induced endothelial motility and angiogenesis were counteracted by using β-muricholic acid as an FXR antagonist. Moreover, we investigated the efficacy of cholesterol-lowering medications, such as cholestyramine, fenofibrate, and atorvastatin, in regulating LCPF-regulated angiogenesis. Along with suppressing endothelial proliferation and angiogenesis, atorvastatin treatment reversed cholesterol accumulation and endothelial junction disruption caused by LCPF. Statin treatment inhibited LCPF-induced endothelial FXR expression as well as the downstream proteins RXR and SHP. Based on the positive findings of suppressing endothelial angiogenesis, our group further incorporated the effect of statin on clinical patients complicated with LCPF. A Kaplan–Meier analysis revealed the clinical benefit of statin exposure in patients with lung adenocarcinoma with LCPF. Conclusively, our study demonstrated the ability of statin to alleviate LCPF-induced angiogenesis in patients with LCPF via FXR modulation.

Overcoming Resistance in Prostate Cancer Therapy Using a DZ-Simvastatin Conjugate

“…Statins exhibit chemopreventive effects against cancer. These drugs inhibit both cancer cell lines and animal tumor models − by promoting cell cycle arrest, inducing cancer cell apoptosis, , and suppressing angiogenesis. , With over three decades of use in treating hyperlipidemia, statins have a well-documented safety profile. − However, when used as monotherapies, statins have shown limited efficacy in cancer treatment, especially against metastatic tumors. Delivering statins with tumor-cell targeting vehicles may increase their antitumor efficacy.…”

Role of Endothelial Cell Metabolism in Normal and Tumor Vasculature

“…This Special Issue of Cancers , dedicated to the “Role of Endothelial Cell Metabolism in Normal and Tumor Vasculature”, resulted in a total of six published articles, including one original research article and five review articles. In their research article, Tsai and collaborators investigated the role of bile acid signaling in pleural angiogenesis [ 15 ]. This study reveals a correlation between elevated bile acid levels and the increased expression of the bile acid farnesoid X receptor (FXR).…”