title: 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.
authors.affiliation: Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Urszula M
authors.initials: UM
authors.lastname: Domanska
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.forename: Wouter B
authors.initials: WB
authors.lastname: Nagengast
authors.forename: Thijs H
authors.initials: TH
authors.lastname: Oude Munnink
authors.forename: Roeliene C
authors.initials: RC
authors.lastname: Kruizinga
authors.forename: Hildo J K
authors.initials: HJ
authors.lastname: Ananias
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Kliphuis
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: De Vries
authors.forename: Igle J
authors.initials: IJ
authors.lastname: de Jong
authors.forename: Annemiek M E
authors.initials: AM
authors.lastname: Walenkamp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D000077143:Docetaxel; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D043823:Taxoids; D000077143:Docetaxel; C088327:plerixafor