Pitavastatin slows tumor progression and alters urine-derived volatile organic compounds through the mevalonate pathway

FASEB J. 2019 Dec;33(12):13710-13721. doi: 10.1096/fj.201901388R. Epub 2019 Oct 4.


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 γ, 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: VOC; bone metastasis; breast cancer; osteoclasts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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, Inbred BALB C
  • Osteoblasts / metabolism
  • Quinolines / pharmacology*
  • RAW 264.7 Cells
  • Volatile Organic Compounds / metabolism*


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Quinolines
  • Volatile Organic Compounds
  • pitavastatin
  • Mevalonic Acid