Pyrrolopyrimidine c-Src inhibitors reduce growth, adhesion, motility and invasion of prostate cancer cells in vitro.
Two bona fide c-Src inhibitors, denominated CGP77675 and CGP76030, reduced in a time- and concentration-dependent manner (i) the proliferation of the PC3 prostate carcinoma cell line, as assessed by the [3H]-thymidine incorporation test, (ii) the capacity of PC3 cells to adhere and spread on Matrigel substrate, as determined by crystal violet staining, (iii) the ability of PC3 cells to migrate through a gelatine boundary and invade a Matrigel substrate. The latter effect was not due to a decrease of urokinase-type plasminogen activator (uPA), nor of metalloproteinase-2 (MMP-2) activities. The MMP-9 activity, along with the expression of the Tissue Inhibitor of Metalloproteinases (TIMP)-1 and TIMP-2, were reduced by the two inhibitors, consistent with the ability of c-Src to enhance MMP-9 and TIMP expression levels. Collectively, these data demonstrate that the pyrrolopyrimidine-derived c-Src inhibitors significantly reduced PC3 cell activities associated with their malignant phenotype.
Recchia
I
I
Department of Experimental Medicine, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy.
Rucci
N
N
Festuccia
C
C
Bologna
M
M
MacKay
A R
AR
Migliaccio
S
S
Longo
M
M
Susa
M
M
Fabbro
D
D
Teti
A
A
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C472714:CGP 76030; D011743:Pyrimidines; D011758:Pyrroles; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020782:Matrix Metalloproteinases; C119957:CGP 77675