Ipriflavone inhibits osteolytic bone metastasis of human breast cancer cells in a nude mouse model.
Osteolytic bone metastasis is a frequent problem in the treatment of cancer. Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used for the treatment of osteoporosis in some countries. Some other isoflavones also exhibit an antitumor effect in vitro and in vivo. Here, we studied the effects of ipriflavone on osteolytic bone metastasis of MDA-231 human breast cancer cells injected intracardially into athymic nude mice (ICR-nu/nu). Daily oral administration of ipriflavone at 12 mg/mouse significantly inhibited the development of new osteolytic bone metastases (p < 0.05) and the progression of established osteolytic lesions (p = 0.01), prolonging the life of tumor-bearing mice (p = 0.01 vs. control). In addition, ipriflavone reduced the number of osteoclasts at the bone-cancer interface with no severe adverse effects on the host. In vitro, ipriflavone inhibited the proliferation and DNA synthesis of MDA-231 cells and blocked the ligand-induced phosphorylation of Tyr(845) of the EGFR. Ipriflavone did not promote apoptosis of MDA-231 cells. Our results show that ipriflavone not only directly inhibits the growth of cancer cells but also reduces osteoclasts to prevent the soft tissue tumor burden and osteolytic bone metastases. These findings raise the possibility that ipriflavone may be of use as a therapeutic agent against osteolytic bone metastasis.
Iwasaki
Teruo
T
First Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. teruteru@hyo-med.ac.jp
Mukai
Mutsuko
M
Tsujimura
Tohru
T
Tatsuta
Masaharu
M
Nakamura
Hiroyuki
H
Terada
Nobuyuki
N
Akedo
Hitoshi
H
D000700:Analgesics / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D007529:Isoflavones / Q000009:adverse effects / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008940:Mitotic Index; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D016896:Treatment Outcome; D014443:Tyrosine / Q000378:metabolism
D000700:Analgesics; D000970:Antineoplastic Agents; D007529:Isoflavones; D014443:Tyrosine; C018986:ipriflavone; D066246:ErbB Receptors