Antiangiogenic and antitumor effects of SRC inhibition in ovarian carcinoma.
Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma.
Han
Liz Y
LY
Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Landen
Charles N
CN
Trevino
Jose G
JG
Halder
Jyotsnabaran
J
Lin
Yvonne G
YG
Kamat
Aparna A
AA
Kim
Tae-Jin
TJ
Merritt
William M
WM
Coleman
Robert L
RL
Gershenson
David M
DM
Shakespeare
William C
WC
Wang
Yihan
Y
Sundaramoorth
Raji
R
Metcalf
Chester A
CA
Dalgarno
David C
DC
Sawyer
Tomi K
TK
Gallick
Gary E
GE
Sood
Anil K
AK
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C508187:AP23846; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate; D004492:Edetic Acid; D019061:src-Family Kinases