Anticancer effects of zoledronic acid against human osteosarcoma cells.
Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.
Kubista
B
B
Department of Orthopaedics, Vienna General Hospital and Medical University of Vienna, Vienna, Austria.
Trieb
K
K
Sevelda
F
F
Toma
C
C
Arrich
F
F
Heffeter
P
P
Elbling
L
L
Sutterlüty
H
H
Scotlandi
K
K
Kotz
R
R
Micksche
M
M
Berger
W
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D005204:Farnesol / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017368:Protein Prenylation / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology; D000077211:Zoledronic Acid
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004164:Diphosphonates; D004338:Drug Combinations; D007093:Imidazoles; D013729:Terpenes; D005204:Farnesol; D000077211:Zoledronic Acid; D004247:DNA