title: Inhibition of tumor growth and histopathological changes following treatment with a chemokine receptor CXCR4 antagonist in a prostate cancer xenograft model.
abstract: The stromal derived factor-1 (SDF-1)/CXCR4 axis is associated with tumor aggressiveness and metastasis in prostate cancer. The present study aimed to explore the potential therapeutic effects of a CXCR4 antagonist in prostate cancer. The effect of SDF-1 and a CXCR4-specific antagonist, AMD3100, on human prostate cancer PC-3 cell proliferation and protein kinase B (Akt) signaling was assessed. Moreover, a PC-3 tumor xenograft model was used to evaluate the effect of AMD3100 on tumor growth and to identify the histopathological changes and immunohistochemical differences between AMD3100-treated and untreated groups. Cell proliferation was not significantly affected by SDF-1 or AMD3100 treatmentin vitro. Western blot analysis revealed that SDF-1 stimulation enhanced the expression of phosphorylated Akt in the PC-3 cells, but that the SDF-1-induced expression of phosphorylated Akt was abrogated in the AMD3100-treated PC-3 cells. In the PC-3 tumor xenograft model, AMD3100 significantly inhibited tumor growth, while AMD3100-treated PC-3 tumors had lower levels of microvessel formation and a lower immunoreactivity for the proliferation marker Ki-67 and the anti-apoptotic marker Bcl-2 compared to control tumorsin vivo. The CXCR4-specific antagonist inhibits SDF-1-induced CXCR4/Akt signal transduction, and effectively suppresses tumor growth in the PC-3 xenograft model. The present study indicates that CXCR4 targeting may represent a novel strategy for the treatment of castration-resistant prostate cancer (CRPC).
authors.affiliation: Department of Urology and Urological Science Institute, Severance Hospital, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Kang Su
authors.initials: KS
authors.lastname: Cho
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Joo Yong
authors.initials: JY
authors.lastname: Lee
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Cho
authors.forename: Young Deuk
authors.initials: YD
authors.lastname: Choi
authors.forename: Yun Seob
authors.initials: YS
authors.lastname: Song
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Hong
keywords: CXCL12; CXCR4; chemokine; prostatic neoplasms; receptors