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Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment

Authors
 Se Young Park  ;  Hyun-Jeong Kim  ;  Ki Rim Kim  ;  Sun Kyoung Lee  ;  Chang Ki Lee  ;  Kwang-Kyun Park  ;  Won-Yoon Chung 
Citation
 Toxicology and Applied Pharmacology, Vol.275(2) : 152-162, 2014 
Journal Title
 Toxicology and Applied Pharmacology 
ISSN
 0041-008X 
Issue Date
2014
Abstract
Many breast cancer patients experience bone metastases and suffer skeletal complications. The present study provides evidence on the protective and therapeutic potential of betulinic acid on cancer-associated bone diseases. Betulinic acid is a naturally occurring triterpenoid with the beneficial activity to limit the progression and severity of cancer, diabetes, cardiovascular diseases, atherosclerosis, and obesity. We first investigated its effect on breast cancer cells, osteoblastic cells, and osteoclasts in the vicious cycle of osteolytic bone metastasis. Betulinic acid reduced cell viability and the production of parathyroid hormone-related protein (PTHrP), a major osteolytic factor, in MDA-MB-231 human metastatic breast cancer cells stimulated with or without tumor growth factor-β. Betulinic acid blocked an increase in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin ratio by downregulating RANKL protein expression in PTHrP-treated human osteoblastic cells. In addition, betulinic acid inhibited RANKL-induced osteoclastogenesis in murine bone marrow macrophages and decreased the production of resorbed area in plates with a bone biomimetic synthetic surface by suppressing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Furthermore, oral administration of betulinic acid inhibited bone loss in mice intra-tibially inoculated with breast cancer cells and in ovariectomized mice causing estrogen deprivation, as supported by the restored bone morphometric parameters and serum bone turnover markers. Taken together, these findings suggest that betulinic acid may have the potential to prevent bone loss in patients with bone metastases and cancer treatment-induced estrogen deficiency.
Full Text
http://www.sciencedirect.com/science/article/pii/S0041008X14000179
DOI
10.1016/j.taap.2014.01.009
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
김기림(Kim, Ki Rim)
김현정(Kim, Hyun-Jeong) ORCID logo https://orcid.org/0000-0003-4608-2120
박광균(Park, Kwang Kyun)
이선경(Lee, Sun Kyoung) ORCID logo https://orcid.org/0000-0002-3707-8050
이창기(Lee, Chang Ki)
정원윤(Chung, Won Yoon) ORCID logo https://orcid.org/0000-0001-8428-9005
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98215
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