Chemotherapeutic effect of calcidiol derivative B3CD in a neuroblastoma xenograft model.
Bromoacetoxy-calcidiol (B3CD), a pro-apoptotic and cytotoxic agent in neuroblastoma (NB) cell lines, displayed therapeutic potential in vivo as an anticancer drug in a NB xenograft mouse model. Tumors of all animals treated intraperitoneally with B3CD went into regression within 10-30 days of treatment, while tumors in control animals grew aggressively. The response mechanisms of NB cells to B3CD in vitro were studied and included differential targeting of cell cycle key regulators p21 and cyclin D1 on the transcriptional and expression level leading to arrest in G0/G1 phase. In contrast to the effect in ovarian cancer cells, B3CD-induced cell death in SMS-KCNR NB cells was only marginally mediated by the p38 MAPK signaling pathway. Signaling induced by exogenous recombinant EGF leads to a partial restoration of the negative effects of B3CD on SMS-KCNR cell proliferation and survival. Upon combinational treatment of SMS-KCNR cells with B3CD and recombinant EGF, the EGF receptor (EGF-R) was highly activated. We suggest future studies to include analysis of the effects of B3CD in combination therapy with pharmacological inhibitors of cell cycle regulators or with EGF-R-targeting inhibitors, -toxins or -antibodies in vitro and their translation into in vivo models of tumor development.
Lange
Thilo S
TS
Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital of RI, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.
Zou
Yongping
Y
Singh
Rakesh K
RK
Kim
Kyu K
KK
Kristjansdottir
Katrin
K
Sholler
Giselle L S
GL
Brard
Laurent
L
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016193:G1 Phase; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy*; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C552951:3-bromoacetoxycalcidiol; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases; D002112:Calcifediol