Effects of CXCR4 antagonist CTCE-9908 on prostate tumor growth.
BACKGROUND
Recent reports have linked the survival-promoting effect of CXCR4 to the up regulation of Bcl-2 protein expression.


METHODS
To further elucidate the relationship between Bcl-2 and CXCR4, tumorigenicity was evaluated in in vitro and in vivo models following treatment with CTCE-9908, a CXCR4 antagonist peptide.


RESULTS
In vitro, CTCE-9908 inhibited cellular proliferation in PC-3-Bcl-2 and PC-3-Neo cell lines Furthermore in our xenograft model, CTCE-9908 delivered via daily intraperitoneal injections resulted in a statistically significant reduction in tumor size compared to control (396 + 205 mm(3) vs. 1,010 + 215 mm(3) respectively, p < 0.05) in the Bcl-2 expressing tumors. This reduction was associated with knockdown of VEGF, inhibition of angiogenesis and lymphangiogenesis, and induction of apoptosis. CTCE-9908 therapy was also associated with a marked reduction in intra-tumoral host cells expressing VEGFR1 and CD11b myeloid-derived suppressor cells (MDSC).


CONCLUSIONS
These data show that CXCR4 antagonists represent a valuable addition to the cancer therapeutic arsenal. Such agents may have beneficial synergistic dual-effects in reducing tumor cell proliferation directly, and indirectly through perturbation of the tumor microenvironment. Further studies of the novel CTCE-9908 compound in prostate and other solid tumor inhibition are warranted. Prostate 69: 1460-1469, 2009. (c) 2009 Wiley-Liss, Inc.
Porvasnik
Stacy
S
Department of Urology, University of Florida, Gainesville, Florida, USA.
Sakamoto
Noboru
N
Kusmartsev
Sergei
S
Eruslanov
Evgeniy
E
Kim
Wan-Ju
WJ
Cao
Wengang
W
Urbanek
Cydney
C
Wong
Donald
D
Goodison
Steve
S
Rosser
Charles J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010455:Peptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D039481:CD11b Antigen; C540323:CTCE-9908; C527276:CXCR4 protein, human; D010455:Peptides; D019718:Receptors, CXCR4; D040281:Vascular Endothelial Growth Factor Receptor-1; D051057:Proto-Oncogene Proteins c-akt