Publications (2)7.15 Total impact
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Article: Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer.
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ABSTRACT: Rapamycin analogs temsirolimus and everolimus have been approved for the treatment of advanced renal cancer and are being tested in a wide spectrum of human tumors. However, objective response rates with rapalogs in clinical trials were modest and variable. Identification of biomarkers capable of predicting response to rapalogs is of increasing interest. We analyzed pairwise Pearson correlation coefficients (r) between rapalogs activity and gene expression profile for each NCI-60 cell line. p27 showed the highest positive correlation among 9,706 gene probes tested. At cellular levels, breast cancer MCF-7, T47D, and BT-474 cells, expressing high levels of p27, were sensitive to rapalogs, whereas the cells expressed low levels of p27, such as MDA-MB-231, MDA-MB-468, and MDA-MB-435 cells, exhibited resistance to rapalogs. Mechanistic study indicated that this correlation is likely determined by the basal level of p27 regardless of the phosphorylation or redistribution of p27 upon rapalogs treatment, which may provide a putative threshold to block G1/S transition. Consistently, down-regulation of p27 by siRNA conferred MCF-7 and BT-474 cells insensitive to rapalogs. Moreover, a significant positive correlation between p27 gene expression and rapamycin anti-tumor activity was also observed in mice bearing different human cancer cell xenografts. In conclusion, p27 expression level is positively correlated with the anticancer activity of rapalogs in vitro and in vivo. We propose p27 expression level may be also a candidate predictive biomarker for patient selection for rapalogs-based therapy, which requires clinical validation in a series of patients treated with rapalogs.Journal of Molecular Medicine 09/2010; 88(9):941-52. · 4.67 Impact Factor -
Article: 3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design.
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ABSTRACT: Cytochrome P450 2C19 (CYP2C19) is a member of the cytochrome P-450 enzyme superfamily and plays an important role in the metabolism of drugs. In order to gain insights for developing personalized drugs, the 3D (dimensional) structure of CYP2C19 has been developed based on the crystal structure of CYP2C9 (PDB code 1R90), and its structure-activity relationship with the ligands of CEC, Fluvoxamine, Lescol, and Ticlopidine investigated through the structure-activity relationship approach. By means of a series of docking studies, the binding pockets of CYP2C19 for the four compounds are explicitly defined that will be very useful for conducting mutagenesis studies, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs.Biochemical and Biophysical Research Communications 05/2007; 355(2):513-9. · 2.48 Impact Factor
