Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells.
Breast cancer has a propensity to metastasize to bone, thus causing pathological fractures. Bisphosphonates are established drugs in the treatment of bone metastasis that inhibit osteoclast activity and interrupt the vicious cycle of osteoclast-tumor cell interactions. We evaluated the direct effects of zoledronic acid on estrogen receptor (ER)-negative MDA-MB-231 and ER-positive MCF-7 breast cancer cells. While zoledronic acid (100 microM) inhibited MDA-MB-231 cell proliferation after 72 h, and induced apoptosis via activation of caspase-3 and -7, it had only minor effects on MCF-7 cells. In addition, zoledronic acid induced apoptosis by up-regulating TNF-related apoptosis-inducing ligand (TRAIL) in MDA-MB-231 cells (p<0.01), but had no effect on the expression of its decoy receptor osteoprotegerin (OPG). In MCF-7 cells, both cytokines were suppressed by zoledronic acid. In conclusion, zoledronic acid enhanced the TRAIL-to-OPG ratio in TRAIL-sensitive MDA-MB-231 cells, indicating that the TRAIL/OPG cytokine system is a bisphosphonate-responsive target in breast cancer.
Rachner
Tilman D
TD
Division of Gastroenterology and Endocrinology, Department of Medicine, Philipps-University, Marburg, Germany.
Singh
Shiv K
SK
Schoppet
Michael
M
Benad
Peggy
P
Bornhäuser
Martin
M
Ellenrieder
Volker
V
Ebert
Regina
R
Jakob
Franz
F
Hofbauer
Lorenz C
LC
D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D053244:Osteoprotegerin / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D053244:Osteoprotegerin; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077211:Zoledronic Acid