CXCR4 Inhibition with AMD3100 Sensitizes Prostate Cancer to Docetaxel Chemotherapy

Abstract

Several in vitro and in vivo models have revealed the key role of CXCR4/CXCL12 axis in tumor-stroma interactions. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4-expressing cancer cells. This specific prosurvival influence of stromal cells on tumor cells is thought to protect them from cytotoxic chemotherapy and is postulated as a possible explanation for the minimal residual disease in hematological and solid cancers. Therefore, CXCR4/CXCL12 signaling is an attractive therapeutic target in cancer, as proven in preclinical leukemia mouse models, where CXCR4 inhibition sensitized cancer cells to conventional chemotherapy. This study investigates whether inhibition of CXCR4 with the specific inhibitor AMD3100 sensitizes human prostate cancer cells to docetaxel. We showed that both mouse and human stromal cell lines have a protective effect on PC3-luc cells by promoting their survival after chemotherapy. Furthermore, we demonstrated that AMD3100 sensitizes PC3-luc cells to docetaxel. In a subcutaneous xenograft mouse model of human prostate carcinoma, we showed that a combination of docetaxel and AMD3100 exerts increased antitumor effect compared with docetaxel alone. We concluded that CXCR4 inhibition chemosensitizes prostate cancer cells, both in vitro and in vivo. To explore the relevance of these findings, we analyzed CXCR4 expression levels in human prostate cancer samples. We found that cancer cells present in bone metastatic lesions express higher CXCR4 levels relative to the cells present in primary tumors and lymph node metastatic lesions. These findings underscore the potential of CXCR4 inhibitors as chemosensitizing agents.

CXCR4 Ligands: The Next Big Hit?

“…CXCR4 antagonists have also been evaluated for inhibition of the cross talk between tumor and stromal cells and for mobilization of cancer cells from the protective microenvironment of solid tumors, making them more sensitive to conventional chemotherapy or radiotherapy and antiangiogenic therapy (3,34,(47)(48)(49).…”

Fibroblast heterogeneity in the cancer wound

“…The CXCR4 antagonist AMD3100 was shown to chemosensitize prostate cancer cells to the chemotherapeutic agent docetaxel in a synergistic manner (Domanska et al, 2012). As discussed previously, CXCL12 secreted from FAP-positive cells was shown to be important for immune suppression in pancreatic cancer, providing a conceivable explanation as to why immunological checkpoint antagonists, such as anti-PDL1, have failed in pancreatic cancer (Royal et al, 2010).…”

“…The CXCL12-CXCR4 signaling axis has been shown to mediate chemotherapy resistance (Singh et al, 2010;Domanska et al, 2012), and furthermore, pancreatic stellate cells drive resistance to chemotherapyinduced apoptosis and radiation-induced apoptosis via a mechanism involving activation of the AKT pathway (Hwang et al, 2008). As mentioned earlier, CAFs also secrete factors that stimulate neoplastic cells to undergo EMT and this process has also been shown to augment resistance to chemotherapy (Wang et al, 2009b).…”

“…CXCL12 provides stimulatory input to CXCR4-expressing neoplastic cells, resulting in proliferation and migration (Domanska et al, 2012). In pancreatic cancer cells, CXCL12/CXCR4 signaling triggers invasion and EMT through noncanonical Hedgehog pathway (Li et al, 2012c) and further contributes to cancer progression by activation of the canonical Wnt pathway (Wang et al, 2008).…”

Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells

“…Interestingly, human prostate tissues, primary cultures of prostate epithelial cells from adenocarcinomas and PCa cell lines express membrane-bound CXCR4 (Vaday et al 2004). Moreover, inhibition of CXCR4 reduced aggressiveness and chemosensitized PCa cells in vitro and in vivo (Dessein et al 2010, Domanska et al 2012. Thus, combination therapies targeting the CD74/CXCR4/MIF axis may be valuable to interfere with cancer development.…”