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

Se Young Park, Hyun Jeong Kim, Ki Rim Kim, Sun Kyoung Lee, Chang Ki Lee, Kwang Kyun Park, WonYoon Chung

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)152-162
Number of pages11
JournalToxicology and Applied Pharmacology
Volume275
Issue number2
DOIs
Publication statusPublished - 2014 Mar 1

Fingerprint

Bone Neoplasms
Bone
RANK Ligand
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Parathyroid Hormone-Related Protein
Osteoclasts
Cells
Therapeutics
Estrogens
Cathepsin K
Osteoprotegerin
Biomimetics
Bone Remodeling
Bone Diseases
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
betulinic acid
Osteogenesis

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Cite this

Park, Se Young ; Kim, Hyun Jeong ; Kim, Ki Rim ; Lee, Sun Kyoung ; Lee, Chang Ki ; Park, Kwang Kyun ; Chung, WonYoon. / Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment. In: Toxicology and Applied Pharmacology. 2014 ; Vol. 275, No. 2. pp. 152-162.
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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.",
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Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment. / Park, Se Young; Kim, Hyun Jeong; Kim, Ki Rim; Lee, Sun Kyoung; Lee, Chang Ki; Park, Kwang Kyun; Chung, WonYoon.

In: Toxicology and Applied Pharmacology, Vol. 275, No. 2, 01.03.2014, p. 152-162.

Research output: Contribution to journalArticle

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AU - Kim, Hyun Jeong

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AU - Lee, Chang Ki

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