Preclinical ReportsCholesterol-lowering drug pitavastatin targets lung cancer and angiogenesis via suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signalingHu, Tianjun; Shen, Haibo; Huang, Hongbo; Yang, Zhenhua; Zhou, Yinjie; Zhao, GuofangAuthor Information Department of Thoracic Surgery, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China Received 2 May 2019 Revised form accepted 4 December 2019 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.anti-cancerdrugs.com. Correspondence to Guofang Zhao, MD, Department of Thoracic Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, 41 Xibei St. Haishu District, Ningbo City, Zhejiang Province 315012, China, Tel: +8613907668637; fax: +86 057483617345; e-mail: email@example.com Anti-Cancer Drugs: April 2020 - Volume 31 - Issue 4 - p 377-384 doi: 10.1097/CAD.0000000000000885 Buy SDC Metrics Abstract Therapeutic agents that target both tumor cell and vascular endothelial cell may achieve additional anti-tumor efficacy, particularly in lung cancer due to the critical roles of angiogenesis during lung cancer progression and metastasis. In this work, we showed that pitavastatin, a novel cholesterol-lowering drug, potently inhibited lung cancer cells and angiogenesis. This was achieved by the induction of apoptosis and inhibition of proliferation of lung cancer cells and human lung tumor-associated endothelial cell. Pitavastatin was not only effective to chemo-sensitive but also chemo-resistant lung cancer cells. This was also consistent with the finding that pitavastatin significantly enhanced cisplatin’s efficacy in lung cancer xenograft model without causing toxicity in mice. We further showed that pitavastatin inhibited lung tumor angiogenesis in vitro and in vivo through suppressing human lung tumor-associated endothelial cell migration and morphogenesis without affecting adhesion. Mechanistically, we showed that pitavastatin acted on lung cancer cells and human lung tumor-associated endothelial cell through suppressing prenylation-dependent Ras/Raf/MEK and PI3K/Akt/mTOR signaling. Our work is the first to demonstrate the inhibitory effects of pitavastatin on Ras-mediated signaling. Our findings provide pre-clinical evidence to repurpose pitavastatin for the treatment of lung cancer. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.