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FASEB J

Title:		Pitavastatin slows tumor progression and alters urine-derived volatile organic compounds through the mevalonate pathway
Author(s):		Wang L; Wang Y; Chen A; Teli M; Kondo R; Jalali A; Fan Y; Liu S; Zhao X; Siegel A; Minami K; Agarwal M; Li BY; Yokota H;
Address:		"Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China. Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA. Osaka University Graduate School of Medicine, Suita, Japan. Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. Integrated Nanosystems Development Institute, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA. Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA. Department of Mechanical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA. Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA. Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, Indiana, USA"
Journal Title:		FASEB J
Year:		2019
Volume:		20191004
Issue:		12
Page Number:		13710 - 13721
DOI:		10.1096/fj.201901388R
ISSN/ISBN:		1530-6860 (Electronic) 0892-6638 (Print) 0892-6638 (Linking)
Abstract:		"Bone is a frequent site of metastasis from breast cancer, and a desirable drug could suppress tumor growth as well as metastasis-linked bone loss. Currently, no drug is able to cure breast cancer-associated bone metastasis. In this study, we focused on statins that are known to inhibit cholesterol production and act as antitumor agents. After an initial potency screening of 7 U.S. Food and Drug Administration-approved statins, we examined pitavastatin as a drug candidate for inhibiting tumor and tumor-induced bone loss. In vitro analysis revealed that pitavastatin acted as an inhibitor of tumor progression by altering stress to the endoplasmic reticulum, down-regulating peroxisome proliferator-activated receptor gamma, and reducing Snail and matrix metalloproteinase 9. In bone homeostasis, it blocked osteoclast development by suppressing transcription factors c-Fos and JunB, but stimulated osteoblast mineralization by regulating bone morphogenetic protein 2 and p53. In a mouse model, pitavastatin presented a dual role in tumor inhibition in the mammary fat pad, as well as in bone protection in the osteolytic tibia. In mass spectrometry-based analysis, volatile organic compounds (VOCs) that were linked to lipid metabolism and cholesterol synthesis were elevated in mice from the tumor-grown placebo group. Notably, pitavastatin-treated mice reduced specific VOCs that are linked to lipid metabolites in the mevalonate pathway. Collectively, the results lay a foundation for further investigation of pitavastatin's therapeutic efficacy in tumor-induced bone loss, as well as VOC-based diagnosis of tumor progression and treatment efficacy.-Wang, L., Wang, Y., Chen, A., Teli, M., Kondo, R., Jalali, A., Fan, Y., Liu, S., Zhao, X., Siegel, A., Minami, K., Agarwal, M., Li, B.-Y., Yokota, H. Pitavastatin slows tumor progression and alters urine-derived volatile organic compounds through the mevalonate pathway"
Keywords:		"Animals Bone Neoplasms/metabolism Breast Neoplasms/metabolism Cell Line Cell Line, Tumor Down-Regulation/physiology Female Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors/metabolism Lipid Metabolism/physiology Mevalonic Acid/*metabolism Mice Mice, I;"
Notes:		"MedlineWang, Luqi Wang, Yue Chen, Andy Teli, Meghana Kondo, Rika Jalali, Aydin Fan, Yao Liu, Shengzhi Zhao, Xinyu Siegel, Amanda Minami, Kazumasa Agarwal, Mangilal Li, Bai-Yan Yokota, Hiroki eng R01 AR052144/AR/NIAMS NIH HHS/ R03 CA238555/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2019/10/06 FASEB J. 2019 Dec; 33(12):13710-13721. doi: 10.1096/fj.201901388R. Epub 2019 Oct 4"