Anti-cancer effects of bortezomib against chemoresistant neuroblastoma cell lines in vitro and in vivo.
The proteasome inhibitor bortezomib (Velcade) was recently approved for the treatment of therapy-refractive multiple myeloma and is under investigation for numerous other types of cancer. A phase I clinical trial in paediatric patients resulted in tolerable toxicity. Since the emergence of chemoresistance represents one of the major drawbacks in cancer therapy, we investigated the influence of bortezomib on multi-drug resistant human neuroblastoma cell lines characterised by P-glycoprotein expression and p53 mutation. Nanomolar concentrations of bortezomib inhibited the cell cycle and induced apoptosis in chemosensitive as well as in chemoresistant cell lines. In vivo growth of chemosensitive and chemoresistant neuroblastoma cell lines was inhibited to a similar extent. In addition, bortezomib inhibited vessel formation in neuroblastoma xenografts. These findings and the favourable toxicity profile of bortezomib in children make it reasonable to further pursue additional development of the drug for the treatment of neuroblastoma and other paediatric solid tumours.
Michaelis
Martin
M
Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, D-60596 Frankfurt am Main, Germany.
Fichtner
Iduna
I
Behrens
Diana
D
Haider
Wolfram
W
Rothweiler
Florian
F
Mack
Andreas
A
Cinatl
Jaroslav
J
Doerr
Hans Wilhelm
HW
Cinatl
Jindrich
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009447:Neuroblastoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D014750:Vincristine; D000069286:Bortezomib; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease