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Targeting SRC and tubulin in mucinous ovarian carcinoma.

ABSTRACT: 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 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.

SUBMITTER: Liu T

PROVIDER: S-EPMC3852199 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Targeting SRC and tubulin in mucinous ovarian carcinoma.

Liu Tao T Hu Wei W Dalton Heather J HJ Choi Hyun Jin HJ Huang Jie J Kang Yu Y Pradeep Sunila S Miyake Takahito T Song Jian H JH Wen Yunfei Y Lu Chunhua C Pecot Chad V CV Bottsford-Miller Justin J Zand Behrouz B Jennings Nicholas B NB Ivan Cristina C Gallick Gary E GE Baggerly Keith A KA Hangauer David G DG Coleman Robert L RL Frumovitz Michael M Sood Anil K AK

Clinical cancer research : an official journal of the American Association for Cancer Research 20131007 23

<h4>Purpose</h4>To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.<h4>Experimental design</h4>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.<h4>Results</h4>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 enhance ...[more]

PMID: 24100628

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Project description:ObjectiveMucinous borderline ovarian tumor (mucinous-BOT) and invasive well-differentiated mucinous ovarian cancer (mucinous-OC) are often histopathologically misclassified. The objective of this study was to examine differences in clinico-pathological characteristics and outcomes of these two entities.MethodsThis is a retrospective population-based study examining the Surveillance, Epidemiology, and End Results Program from 1988 to 2000. Stage I mucinous-BOTs and stage I well-differentiated mucinous-OC were compared for patient demographics, tumor characteristics, and outcomes. Propensity score matching and multivariable analysis were used to assess cause-specific survival (CSS).ResultsA total of 2130 mucinous-BOT and 581 mucinous-OC cases were examined for analysis. On multivariable analysis, women with mucinous-OC were more likely to be older, Eastern U.S. residents, and have undergone hysterectomy or lymphadenectomy compared to those with mucinous-BOT, and the number of women diagnosed with mucinous-OC decreased over time (all, P < 0.05). Mucinous-OCs were more likely to be stage T1c and have a smaller tumor size as compared to mucinous-BOT (both, adjusted-P < 0.05). After propensity score matching, women with mucinous-OC had significantly poorer CSS compared to those with mucinous-BOT on multivariable analysis (10-year rates: 92.7% versus 97.5%, adjusted-hazard ratio [HR] 2.03, P = 0.007). Similar results were observed among subgroups for reproductive age, stage T1a disease, large tumor, and unstaged cases (all, P < 0.05).ConclusionStage I mucinous-BOT and stage I invasive well-differentiated mucinous-OC have distinct differences in clinical characteristics and patient survival. The inability to conduct centralized pathology review in our study limits our conclusions given the recognized issue of misclassification of mucinous-BOT and mucinous-OC, but further highlights the importance of making the proper histopathological diagnosis for invasive cancer when the ovarian tumor is of mucinous histology.

Dataset Information

Targeting SRC and tubulin in mucinous ovarian carcinoma.

Publications

Targeting SRC and tubulin in mucinous ovarian carcinoma.

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