TY - JOUR
T1 - Targeting Src and tubulin in mucinous ovarian carcinoma
AU - Liu, Tao
AU - Hu, Wei
AU - Dalton, Heather J.
AU - Choi, Hyun Jin
AU - Huang, Jie
AU - Kang, Yu
AU - Pradeep, Sunila
AU - Miyake, Takahito
AU - Song, Jian H.
AU - Wen, Yunfei
AU - Lu, Chunhua
AU - Pecot, Chad V.
AU - Bottsford-Miller, Justin
AU - Zand, Behrouz
AU - Jennings, Nicholas B.
AU - Ivan, Cristina
AU - Gallick, Gary E.
AU - Baggerly, Keith A.
AU - Hangauer, David G.
AU - Coleman, Robert L.
AU - Frumovitz, Michael
AU - Sood, Anil K.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - Purpose: To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental Design: Thein vitro and invivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. Results: In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2-M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. Conclusion: Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.
AB - Purpose: To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental Design: Thein vitro and invivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. Results: In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2-M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. Conclusion: Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.
UR - https://www.scopus.com/pages/publications/84890288888
U2 - 10.1158/1078-0432.CCR-13-1305
DO - 10.1158/1078-0432.CCR-13-1305
M3 - Article
C2 - 24100628
AN - SCOPUS:84890288888
SN - 1078-0432
VL - 19
SP - 6532
EP - 6543
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -