Growth suppression of ovarian cancer xenografts in nude mice by vitamin D analogue EB1089.
OBJECTIVE
The poor response of advanced epithelial ovarian cancer to current treatments necessitates the development of alternative therapeutic strategies. Inhibition of cancer growth by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] compounds represents an innovative approach for cancer therapy. The current study evaluated the therapeutic potential of a synthetic 1,25(OH)2D3 analogue EB1089 in the treatment of ovarian cancer.


METHODS
The response of human ovarian cancer cells to 1,25(OH)2D3 and EB1089 were first compared in cell growth, gene transcription, and apoptotic assays. Then, nude mice bearing OVCAR3 tumor xenografts were treated with EB1089 at different dosages, and tumor volumes were monitored. The effect of EB1089 and 1,25(OH)2D3 on the level of serum calcium was also examined. After the treatment, tumors were excised and processed for histologic examination, Ki-67 staining, and tissue terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays to evaluate the morphologic, proliferative, and apoptotic changes induced by EB1089, respectively.


RESULTS
The study shows that EB1089 suppresses the in vitro growth of ovarian cancer cells and transcriptionally activates the GADD45 reporter gene more effectively than 1,25(OH)2D3. Clinically more importantly, EB1089 suppresses the growth of OVCAR3 tumor xenografts in nude mice without inducing hypercalcemia. Ki-67 staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis contribute to the EB1089-induced tumor suppression in vivo.


CONCLUSIONS
This study is the first demonstration that ovarian cancer responds positively in vivo to treatment with a 1,25(OH)2D3 compound and thus supports continued development of 1,25(OH)2D3 analogues for possible use as an alternative or complementary therapy for human ovarian cancer.
Zhang
Xiaohui
X
Department of Pathology and Interdisciplinary Oncology, University of South Florida College of Medicine, Programs of Molecular Oncology and Drug Discovery, H. Lee Moffitt Cancer Center, Tampa, Florida, USA.
Jiang
Feng
F
Li
Pengfei
P
Li
Chunrong
C
Ma
Qiuping
Q
Nicosia
Santo V
SV
Bai
Wenlong
W
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D015533:Transcriptional Activation; D000097642:GADD45 Proteins
D000970:Antineoplastic Agents; D002117:Calcitriol; D002118:Calcium; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D000097642:GADD45 Proteins; C078903:seocalcitol