Effects of the proteasome inhibitor bortezomib on osteolytic human prostate cancer cell metastases.
Prostate adenocarcinoma is the most common malignancy diagnosed in males, and bone metastases remain a significant source of morbidity and mortality in this population. The ubiquitin-proteasome cascade is responsible for the degradation of intracellular proteins, and this pathway is thought to play an essential role in the development of malignancies by altering the levels of various proteins involved in the regulation of cell division. Proteasome inhibitors represent a class of chemotherapeutic agents that have been shown to inhibit tumor growth by a number of different mechanisms. Using a murine intratibial injection model, we examined the effects of the proteasome inhibitor bortezomib on the establishment and progression of osteolytic bone lesions induced by human CaP cells (PC-3 cell line). In this study, the intravenous administration of bortezomib (1 mg/kg) did not prevent the initial formation of osteolytic lesions but did appear to inhibit their growth in a time-dependent fashion. In contrast, bortezomib therapy effectively inhibited the establishment and progression of subcutaneous PC-3 tumors, which served as a positive control. These results suggest that proteasome inhibitors such as bortezomib may represent a novel adjunctive therapy for the treatment of osteolytic skeletal metastases, especially when treatment is initiated early during the disease process.
Whang
P G
PG
Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Gamradt
S C
SC
Gates
J J
JJ
Lieberman
J R
JR
D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex