AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes.
c-Src is frequently activated in human malignancies, including colon, breast, and pancreatic carcinomas. Several recent studies have shown that activation of Src family kinases leads to tumor progression and metastasis by increasing cellular migration and invasion, promoting cell growth and survival, and deregulating expression of proangiogenic molecules. Therefore, selective inhibitors of Src are being developed for cancer therapy. In this study, we characterize the biological effects of the novel ATP-based Src family kinase inhibitor, AP23846, in tumor cells with high Src activity. As a lead compound, AP23846 is a potent c-Src kinase inhibitor (IC50 approximately 0.5 nmol/L in vitro, approximately 10-fold more potent than PP2, the most widely used commercially available Src family kinase inhibitor). At concentrations of 1 micromol/L, AP23846 led to complete Src inhibition for 48 hours in cells. No cytotoxicity was observed under these conditions, although proliferation rates were slower. Therefore, this was an excellent inhibitor to examine Src-regulated signaling pathways in tumor cells. AP23846 reduced cellular migration, vascular endothelial growth factor, and interleukin-8 in a dose-dependent fashion in pancreatic adenocarcinoma cells grown in vitro. Correspondingly, cell culture supernatants from L3.6pl pancreatic adenocarcinoma cells pretreated with AP23846 failed to promote migration of hepatic endothelial cells in vitro and failed to support angiogenesis into gel foams implanted s.c. in mice in vivo. These results suggest that Src inhibitors affect biological properties of tumor progression and may be useful as cancer therapeutic agents in more advanced disease.
Summy
Justin M
JM
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
Trevino
Jose G
JG
Lesslie
Donald P
DP
Baker
Cheryl H
CH
Shakespeare
William C
WC
Wang
Yihan
Y
Sundaramoorthi
Raji
R
Metcalf
Chester A
CA
Keats
Jeffrey A
JA
Sawyer
Tomi K
TK
Gallick
Gary E
GE
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010766:Phosphorylation; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C508187:AP23846; D017931:DNA Primers; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000255:Adenosine Triphosphate; D019061:src-Family Kinases