Betulinic acid, a bioactive pentacyclic triterpenoid, inhibits skeletal-related events induced by breast cancer bone metastases and treatment.
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.
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
Se Young
SY
Park
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
Hyun-Jeong
HJ
Kim
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
Ki Rim
KR
Kim
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
Sun Kyoung
SK
Lee
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
Chang Ki
CK
Lee
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. Electronic address: biochelab@yuhs.ac.
Kwang-Kyun
KK
Park
Department of Applied Life Science, The Graduate School, Yonsei University, Seoul 120-749, Republic of Korea; Department of Oral Biology, Oral Cancer Research Institute, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. Electronic address: wychung@yuhs.ac.
Won-Yoon
WY
Chung
D000284:Administration, Oral; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption / Q000517:prevention & control; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004967:Estrogens / Q000172:deficiency / Q000378:metabolism; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D053244:Osteoprotegerin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014315:Triterpenes / Q000008:administration & dosage*; D000094062:Betulinic Acid
D004967:Estrogens; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D053978:Pentacyclic Triterpenes; D053245:RANK Ligand; D014315:Triterpenes; D056657:Cathepsin K; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D000094062:Betulinic Acid
Betulinic acid; Estrogen deficiency; Osteoclastogenesis; Osteolytic bone metastasis; PTHrP; RANKL