Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Genitourinary Medical Oncology, Bioinformatics and Computational Biology, and Cancer Biology; Division of Cancer Medicine; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas; Kinex Pharmaceuticals LLC, New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York; Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei; Department of Gynecology, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, P.R. China.
Clin Cancer Res. 2013 Dec 1;19(23):6532-43. doi: 10.1158/1078-0432.CCR-13-1305. Epub 2013 Oct 7.
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.
研究靶向 Src 和微管蛋白对黏液性卵巢癌的抗肿瘤作用。
在黏液性卵巢癌模型中，研究了抑制 Src 通路和微管聚合的 KX-01 的体外和体内作用及分子机制。
在 RMUG-S 和 RMUG-L 细胞系的体外研究中，KX-01 抑制细胞增殖，诱导细胞凋亡，将细胞周期阻滞在 G2-M 期，并增强 KX-01 敏感细胞系 RMUG-S 中奥沙利铂的细胞毒性。体内研究表明，与未治疗对照组相比，KX-01 显著降低了 RMUG-S 和 RMUG-L 小鼠模型中的肿瘤负担，当 KX-01 与奥沙利铂联合使用时，效果更大。KX-01 单独和联合奥沙利铂均可通过减少体内细胞增殖和诱导细胞凋亡显著抑制肿瘤生长。在 RMUG-L 细胞中的 PTEN 基因敲入实验显示对 KX-01 的反应得到改善。反相蛋白阵列分析显示，除了阻断 Src 家族激酶的下游分子外，KX-01 还激活了急性应激诱导分子。
我们的结果表明，KX-01 靶向 Src 通路和微管蛋白可显著抑制临床前黏液性卵巢癌模型中的肿瘤生长，这表明这可能是治疗黏液性卵巢癌患者的一种有前途的治疗方法。
