Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model.
OBJECTIVE
It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice.


RESULTS
The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 microg/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells.


CONCLUSIONS
These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.
Hiraga
Toru
T
Department of Biochemistry, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.
Williams
Paul J
PJ
Ueda
Akimi
A
Tamura
Daisuke
D
Yoneda
Toshiyuki
T
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002469:Cell Separation; D002470:Cell Survival; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism; D013997:Time Factors; D000077211:Zoledronic Acid
D004164:Diphosphonates; D004224:Diterpenes; D007093:Imidazoles; D000077211:Zoledronic Acid; C017338:geranylgeraniol; D008156:Luciferases