Targeting CXCR4 with CTCE-9908 inhibits prostate tumor metastasis.
BACKGROUND
CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface is thought to mediate tumor growth and subsequent development of metastatic disease. CTCE-9908 is a known inhibitor of CXCR4. Herein, we tested the efficacy of CTCE-9908 in inhibiting prostate cancer cell growth, invasion, and metastasis.


METHODS
We used a panel of in vitro assays utilizing human prostate cancer cell lines and an in vivo orthotopic prostate cancer model to assess the anti-tumoral activity of CTCE-9908.


RESULTS
We demonstrated that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 and C4-2B cells; (b) 50 μg/ml of CTCE-9908 inhibited the invasive properties of PC-3 cells; (c) 25 mg/kg of CTCE-9908 did not alter primary tumor growth but it did significantly reduce total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues. Histological analysis showed that CTCE-9908 treatment resulted in tumor necrosis in primary prostate tumors and no significant change in proliferation of tumor cells as measured by Ki-67 staining; (d) CTCE-9908 inhibited the tumor angiogenesis as measured by CD34 positive vessels in tumors.


CONCLUSIONS
These data suggest that CXCR4 inhibition by CTCE-9908 decreases the invasion potential in vitro, which then translated to a reduction of tumor spread with associated reduction in angiogenesis. Hence, CTCE-9908 may prove to be an efficacious novel agent to prevent and treat the spread of metastatic prostate cancer.
Donald
D
Wong
Pridvi
P
Kandagatla
Walter
W
Korz
Department of Urology, Wayne State University School of Medicine, 9200 Scott Hall 540 E, Canfield Avenue, Detroit, MI 48201, USA. schinni@med.wayne.edu.
Sreenivasa R
SR
Chinni
D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D010455:Peptides / Q000008:administration & dosage*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000556:secondary*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C540323:CTCE-9908; C527276:CXCR4 protein, human; D010455:Peptides; D019718:Receptors, CXCR4