New HIV-drug inhibits in vitro bladder cancer migration and invasion.
OBJECTIVE
The CXCR4/CXCL12 axis appears crucial in the metastasis of bladder cancer. Our aim was to evaluate the potency of the CXCR4 antagonist, 4F-benzoyl-TE14011 (4F-bTE), as an anti-metastatic drug in this disease. In this study, we assessed the ability of 4F-bTE to inhibit tumor cell motility, invasion through extracellular matrix (ECM), matrix metalloproteinase (MMP) secretion and cytoskeletal responses to chemokine.


METHODS
To assess the degree to which cells could migrate and invade ECM under various conditions, we used TCCSUP bladder cancer cells in a Boyden chamber system. To monitor actin polymerization, we stained cells on chamber slides with AlexaFluor 594 phalloidin. To measure matrix-metalloproteinase-2 and -9 (MMP) activity, we used gelatin zymography. To assess the effects of the CXCR4 antagonist 4F-bTE on each of the above parameters, we exposed bladder cancer cells either to chemokine CXCL12, alone, or to both CXCL12 and 4F-bTE. We also monitored cells for apoptotic and necrotic changes during drug treatment.


RESULTS
The CXCR4 antagonist 4F-bTE markedly decreased CXCL12-induced bladder cancer cell migration and ECM invasion in Boyden chamber assays. The antagonist also blocked chemokine-induced actin polymerization as well as the induction of MMP-2 and MMP-9 in these cells.


CONCLUSIONS
The CXCR4 antagonist 4F-bTE has the potential to inhibit expression of the metastatic phenotype and may provide therapeutic value to patients.
Retz
M
M
Biomolecular Sciences Program, Cardiovascular Research Institute, Department of Anatomy, UCSF, San Francisco, CA 94143-0452, USA.
Sidhu
S S
SS
Lehmann
J
J
Tamamura
H
H
Fujii
N
N
Basbaum
C
C
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019743:Chemokines, CXC / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011336:Probability; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured / Q000166:cytology; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
D019380:Anti-HIV Agents; D019743:Chemokines, CXC; D023063:Receptors, Interleukin-8B