Anti-proliferative and pro-apoptotic properties of 3-bromoacetoxy calcidiol in high-risk neuroblastoma.
The cytotoxic, anti-proliferative and apoptotic effects of 3-Bromoacetoxy Calcidiol (B3CD), a derivative of vitamin D3 precursor calcidiol, on human neuroblastoma (NB) cells were examined. NB, predominantly a tumor of early childhood, is the most common extracranial solid tumor. Despite aggressive treatments, survival for advanced stages remains low and novel treatment strategies are needed. B3CD-induced apoptosis in various neuroblastic cells via caspases-3 and -9 activation. B3CD upregulated mitochondrial pro-apoptotic Bax and anti-apoptotic Bcl-2 expression, caused cytochrome c release, downregulated N-Myc expression and activated pro-survival marker Akt. Accordingly, B3CD treatment dose dependently reduced the viability of NB cells with IC50 values between 1 and 3 microm. The cytotoxicity of B3CD was significantly higher than for the calcemic parent-compound vitamin D3 (IC50 between 10 and 30 microm). Further studies revealed that B3CD treatment inhibits the proliferation of NB cells at low concentrations (IC50 between 30 and 100 nm). Cell cycle analysis showed a dramatic increase in the apoptotic sub-diploidal population along with a cell cycle block. In summary, the present study shows that B3CD is toxic to NB cells via suppression of cell proliferation and cell viability by caspase activation and regulation of survival signals. These results suggest that B3CD could be developed as a treatment for NB.
Lange
Thilo S
TS
Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital of RI, Providence, RI 02905, USA.
Singh
Rakesh K
RK
Kim
Kyu Kwang
KK
Zou
Yongping
Y
Kalkunte
Satyan S
SS
Sholler
Giselle L
GL
Swamy
Narasimha
N
Brard
Laurent
L
D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017605:Bromine Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D015394:Molecular Structure; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology
C552951:3-bromoacetoxycalcidiol; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D017605:Bromine Compounds; D002117:Calcitriol; D002112:Calcifediol