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Dietary Conjugated Linoleic Acids Arrest Cell Cycle Progression and Prevent Ovarian Cancer Xenografts Growth Suggesting a Trans-10 Cis-12 Isoform Specific Activity

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Journal of Cancer Therapy 2013年第5期4卷 33-42页

作者： Philippe Thuillier Nupur T. Pande andrea ghena Shuang Song Yancey Lawrence Vidya Shridhar Yasmine Akkari Tanja Pejovic Susan Olson Cytopathology Lab Legacy Emanuel Hospital Portland USA Knight Cancer Research Institute Oregon Health and Sciences University Portland USA Molecular and Medical Genetics Oregon Health and Science University Portland USA Rich Graviss Pvt. Ltd. India

Therapies for treating ovarian cancer (OvCa) successfully are largely inadequate. Alternative therapies and diet(s) with preventive potential to debilitated onset, and reduced OvCa tumor burden in situ, have not been systematically studied. Preventive role of conjugated linoleic acids (CLAs) has been reported in many other cancers. We report the first systematic in vitro and in vivo study modeling potential preventive mechanism(s) of CLA, an octadecadienolic fatty acid in clear cell OvCa cell line TOV-21G. We demonstrate that a dose and time-dependent down-regulation of cyclin E and A proteins (p 0.05) by CLA (t10,c12) was concomitant with cell cycle arrest of TOV-21G cell lines in S phase. To understand the molecular mechanism underlying CLA (t10,c12) induced S phase arrest, levels of cell cycle regulatory proteins were determined by western blot analyses. Exposure to CLA (t10,c12) increased p21(CIP1/WAF1), and p27(KIP1) protein levels in a time and dose-dependent manner. Interestingly CLA (t10,c12) did not significantly affect protein levels of cyclin-dependent kinase (cdk) 2, and p53, however, hyperphosphorylated form of pRb (p 0.05) was abrogated. Exposure to CLA (c9,t11) indicated a modest increase in p21(CIP1/WAF1) and p27(KIP1) levels, but changes in cyclin A and E levels were statistically insignificant. These results indicate that CLA (t10,c12) mediated p27(KIP1) upregulation and inhibition of hyperphosphorylation of ppRb may be the possible mechanism for the S phase arrest in TOV-21G cell line. Our in vivo data showed that CLA reduced the progression of TOV-21G xenografts by >50%. Together our results provide evidence of CLA exerted preventive effect on OvCa cell and tumor growth. Tumor growth arrest may be resultant from CLA (t10,c12) mediated modulation of cell cycle arrest.

关键词： Dietary Prevention Ovarian Cancer Cell Cycle DNA Damage Tumor Inhibition

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