Targeting Src and Tubulin in Mucinous Ovarian Carcinoma

• Published in: Clinical cancer research 2013-12, Vol.19 (23), p.6532-6543
• Main Authors: TAO LIU, WEI HU, CHUNHUA LU, PECOT, Chad V, BOTTSFORD-MILLER, Justin, ZAND, Behrouz, JENNINGS, Nicholas B, IVAN, Cristina, GALLICK, Gary E, BAGGERLY, Keith A, HANGAUER, David G, COLEMAN, Robert L, DALTON, Heather J, FRUMOVITZ, Michael, SOOD, Anil K, HYUN JIN CHOI, JIE HUANG, YU KANG, PRADEEP, Sunila, MIYAKE, Takahito, SONG, Jian H, YUNFEI WEN
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Acetamides - therapeutic use; Adenocarcinoma, Mucinous - drug therapy; Adenocarcinoma, Mucinous - metabolism; Adenocarcinoma, Mucinous - pathology; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Cell Cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Drug Synergism; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Inhibitory Concentration 50; Medical sciences; Mice; Mice, Nude; Microtubules - metabolism; Morpholines; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Organoplatinum Compounds - pharmacology; Organoplatinum Compounds - therapeutic use; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxaliplatin; Pharmacology. Drug treatments; Protein Multimerization; PTEN Phosphohydrolase - metabolism; Pyridines - pharmacology; Pyridines - therapeutic use; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Tubulin Modulators - pharmacology; Tubulin Modulators - therapeutic use; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-13-1305

To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. 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. 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.