How do bisphosphonates inhibit bone metastasis in vivo?
Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and have demonstrated clinical utility in the treatment of patients with osteolytic bone metastases. They also exhibit direct antitumor activity in vitro and can reduce skeletal tumor burden and inhibit the formation of bone metastases in vivo. However, whether such effects are caused by a direct action of bisphosphonates on tumor cells or indirectly through inhibition of bone resorption remains unclear. To address this question, we used here a structural analog of the bisphosphonate risedronate, NE-58051, which has a bone mineral affinity similar to that of risedronate, but a 3000-fold lower bone antiresorptive activity. In vitro, risedronate and NE-58051 inhibited proliferation of breast cancer and melanoma cell lines. In vivo, risedronate and NE-58051 did not inhibit the growth of subcutaneous B02 breast tumor xenografts or the formation of B16F10 melanoma lung metastasis. In contrast to NE-58051, risedronate did inhibit B02 breast cancer bone metastasis formation by reducing both bone destruction and skeletal tumor burden, indicating that the antitumor effect of bisphosphonates is achieved mainly through inhibition of osteoclast-mediated bone resorption.
Fournier
Pierrick G
PG
Institut National de la Santé et de la Recherche Médicale, UMR 664, IFR62, Lyon, France.
Stresing
Verena
V
Ebetino
Frank H
FH
Clézardin
Philippe
P
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000068296:Risedronic Acid; D023041:Xenograft Model Antitumor Assays
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D011725:Pyridines; C108384:NE 58051; D000068296:Risedronic Acid; D012968:Etidronic Acid