Effect of a vitamin D(3) derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model.
The objective of the present study was to test the hypothesis that Calcidiol derivative B3CD qualifies as a potential anti-cancer drug in vivo employing an ovarian cancer xenograft model in mice. In addition, the selectivity of B3CD on viability and proliferation of platinum-resistant human ovarian cancer cell lines in comparison to control cell lines was analyzed in vitro. B3CD displayed cell line-specific cytotoxicity screened against a panel of ovarian and other carcinoma cell lines, endothelial and control cells. B3CD, at sub-cytotoxic concentrations, revealed stronger effects on the proliferation of SKOV-3 ovarian cancer cells vs. primary fibroblasts as determined by BrdU incorporation analysis. Treatment with B3CD at 0.5 microM resulted in highly condensed chromatin and fragmented nuclei in SKOV-3 cells but not in primary fibroblasts. B3CD induced cell death at low drug concentrations (< or = 0.5 microM) in SKOV-3 ovarian cancer cells is mediated by the p38 MAPK signaling pathway: B3CD induced p38 MAPK expression and activation in SKOV-3 cells and inhibition of p38 signaling counteracted B3CD induced cell death in vitro. An ovarian cancer cell animal model (human SKOV-3 cell derived xenografts in nude mice) revealed that tumor growth in few B3CD treated mice accelerated while the majority of B3CD treated mice displayed delayed tumor growth or full tumor regression. B3CD possesses anti-ovarian cancer properties in vitro and in vivo. We propose the further development of non-calcemic bromoacetoxy derivatives of vitamin D(3) as potential anti-cancer therapeutics.
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.
Stuckey
Ashley R
AR
Robison
Katina
K
Kim
Kyu Kwang
KK
Singh
Rakesh K
RK
Raker
Christina A
CA
Brard
Laurent
L
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002117:Calcitriol / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C552951:3-bromoacetoxycalcidiol; D000970:Antineoplastic Agents; D002762:Cholecalciferol; D048051:p38 Mitogen-Activated Protein Kinases; D002117:Calcitriol; D002112:Calcifediol