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 treatment in 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 tumors in 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).

N-terminal polypeptide derived from vMIP-II exerts its antitumor activity by inhibiting the CXCR4 pathway in human glioma

“…SDF-1α promotes tumor growth in a paracrine fashion by directly stimulating tumor cell proliferation and survival via CXCR4. Moreover, interruption of CXCR4 and SDF-1α axis has demonstrated antitumor growth activities in a variety of preclinical tumor models (6–8). Therefore, it is necessary and of great significance to develop a CXCR4 antagonist targeting CXCR4 for providing more effective strategy for the treatment of glioma.…”

NMMHC-IIA-dependent nuclear location of CXCR4 promotes migration and invasion in renal cell carcinoma

“…CXCR4 chemokine receptor belongs to the group of seven transmembrane G-protein coupled receptors (GPCR) which was found in more than 20 types of tumors in human, including prostate, ovarian and esophageal cancer, melanoma and RCC (8)(9)(10)(11)(12)(13). Growing evidence indicated that high level of CXCR4 was significantly implicated in tumorigenesis and metastasis in many malignancies (14,15). Previous studies have shown that nuclear localized CXCR4 determined prognosis for colon, gastric, lung and colorectal cancer (16)(17)(18)(19).…”

Meta-Analysis of the Relationship between CXCR4 Expression and Metastasis in Prostate Cancer

“…Because metastasis greatly influences the prognosis and treatment of advanced prostate cancer, targeting the SDF-1/CXCR4 axis is a potentially attractive strategy because it emphasizes prevention or delay of metastatic disease. Recent studies have shown promising experimental data, suggesting that CXCR4 antagonism can be an effective modality to control metastatic disease by disrupting the interaction between cancer cells and the protective microenvironment [ 32 , 33 ]. Domanska et al [ 32 ] reported that CXCR4 inhibition sensitizes prostate cancer cells to docetaxel in vitro and in vivo .…”

“…Domanska et al [ 32 ] reported that CXCR4 inhibition sensitizes prostate cancer cells to docetaxel in vitro and in vivo . Cho et al [ 33 ] found that CXCR4 antagonism significantly inhibited microvessel formation and tumor growth in the PC-3 tumor xenograft model as compared to control tumors. In other xenograft models, such as anaplastic thyroid cancer, ovarian cancer, and oral squamous cell cancer, inhibitory effects of CXCR4 antagonism on tumor growth and metastasis have been demonstrated [ 33 ].…”