CXCR4 Inhibition with AMD3100 Sensitizes Prostate Cancer to Docetaxel Chemotherapy

被引:171
作者
Domanska, Urszula M. [1 ]
Timmer-Bosscha, Hetty [1 ]
Nagengast, Wouter B. [1 ]
Munnink, Thijs H. Oude [1 ]
Kruizinga, Roeliene C. [1 ]
Ananias, Hildo J. K. [2 ]
Kliphuis, Nathalie M. [1 ]
Huls, Gerwin [3 ]
De Vries, Elisabeth G. E. [1 ]
de Jong, Igle J. [2 ]
Walenkamp, Annemiek M. E. [1 ]
机构
[1] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, NL-9700 RB Groningen, Netherlands
[2] Univ Med Ctr Groningen, Dept Urol, NL-9700 RB Groningen, Netherlands
[3] Univ Med Ctr Groningen, Dept Haematol, NL-9700 RB Groningen, Netherlands
来源
NEOPLASIA | 2012年 / 14卷 / 08期
关键词
ANTAGONIST CTCE-9908; TUMOR-GROWTH; STEM-CELLS; METASTASIS; LEUKEMIA; AML; CHEMOSENSITIZATION; MICROENVIRONMENT; ANGIOGENESIS; MITOXANTRONE;
D O I
10.1593/neo.12324
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:709 / 718
页数:10
相关论文
共 38 条
[1]  
Andritsos L, 2010, HAEMATOL-HEMATOL J, V95, P321
[2]   CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers [J].
Burger, J. A. ;
Peled, A. .
LEUKEMIA, 2009, 23 (01) :43-52
[3]   Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells [J].
Burger, M ;
Hartmann, T ;
Krome, M ;
Rawluk, J ;
Tamamura, H ;
Fujii, N ;
Kipps, TJ ;
Burger, JA .
BLOOD, 2005, 106 (05) :1824-1830
[4]   Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial [J].
de Bono, Johann Sebastian ;
Oudard, Stephane ;
Ozguroglu, Mustafa ;
Hansen, Steinbjorn ;
Machiels, Jean-Pascal ;
Kocak, Ivo ;
Gravis, Gwenaelle ;
Bodrogi, Istvan ;
Mackenzie, Mary J. ;
Shen, Liji ;
Roessner, Martin ;
Gupta, Sunil ;
Sartor, A. Oliver .
LANCET, 2010, 376 (9747) :1147-1154
[5]   The AMD3100 story: The path to the discovery of a stem cell mobilizer (Mozobil) [J].
De Clercq, Erik .
BIOCHEMICAL PHARMACOLOGY, 2009, 77 (11) :1655-1664
[6]  
DEVRIES EGE, 1989, CANCER RES, V49, P4175
[7]   Plerixafor inhibits chemotaxis toward SDF-1 and CXCR4-mediated stroma contact in a dose-dependent manner resulting in increased susceptibility of BCR-ABL+ cell to Imatinib and Nilotinib [J].
Dillmann, Falk ;
Veldwijk, Marlon R. ;
Laufs, Stephanie ;
Sperandio, Markus ;
Calandra, Gary ;
Wenz, Frederik ;
Zeller, W. Jens ;
Fruehauf, Stefan .
LEUKEMIA & LYMPHOMA, 2009, 50 (10) :1676-1686
[8]   Estimates of cancer incidence and mortality in Europe in 2008 [J].
Ferlay, J. ;
Parkin, D. M. ;
Steliarova-Foucher, E. .
EUROPEAN JOURNAL OF CANCER, 2010, 46 (04) :765-781
[9]   Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis [J].
Franco, Omar E. ;
Jiang, Ming ;
Strand, Douglas W. ;
Peacock, James ;
Fernandez, Suzanne ;
Jackson, Roger S., II ;
Revelo, Monica P. ;
Bhowmick, Neil A. ;
Hayward, Simon W. .
CANCER RESEARCH, 2011, 71 (04) :1272-1281
[10]   DNA Damage-Mediated Induction of a Chemoresistant Niche [J].
Gilbert, Luke A. ;
Hemann, Michael T. .
CELL, 2010, 143 (03) :355-366