Journal
CLINICAL CANCER RESEARCH
Volume 19, Issue 23, Pages 6532-6543Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-1305
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Funding
- National Institutes of Health [P50 CA098258, CA109298, P50 CA083639, CA128797, U54 CA151668]
- CPRIT [RP110595]
- Meyer and Ida Gordon Foundation
- Ovarian Cancer Research Fund, Inc.
- U.S. Department of Defense [OC120547, OC093146]
- Zarrow Foundation
- Marcus Foundation
- Betty Anne Asche Murray Distinguished Professorship
- National Cancer Institute institutional Core Grant [CA16672]
- Laura and John Arnold Foundation
- NCI-DHHS-NIH [T32 CA101642]
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Purpose: To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental Design: 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. 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 G(2)-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. Clin Cancer Res; 19( 23); 6532-43. (C) 2013 AACR.
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