FK506 confers chemosensitivity to anticancer drugs in glioblastoma multiforme cells by decreasing the expression of the multiple resistance-associated protein-1 |
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Authors: | Garrido W Muñoz M San Martín R Quezada C |
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Institution: | aDepartment of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan;bMolecular Pharmacology, St. Jude Children’s Research Hospital, 332 N. Lauderdale St. Memphis, TN 38105-2794, USA |
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Abstract: | Malignant rhabdoid tumor (MRT) is a rare and highly aggressive neoplasm of young children. MRT is characterized by inactivation of integrase interactor 1 (INI1). Cyclin-dependent kinase 4 (CDK4), which acts downstream of INI1, is required for the proliferation of MRT cells. Here we investigated the effects of PD 0332991 (PD), a potent inhibitor of CDK4, against five human MRT cell lines (MP-MRT-AN, KP-MRT-RY, G401, KP-MRT-NS, KP-MRT-YM). In all of the cell lines except KP-MRT-YM, PD inhibited cell proliferation >50%, (IC50 values 0.01 to 0.6 μM) by WST-8 assay, and induced G1-phase cell cycle arrest, as shown by flow cytometry and BrdU incorporation assay. The sensitivity of the MRT cell lines to PD was inversely correlated with p16 expression (r = 0.951). KP-MRT-YM cells overexpress p16 and were resistant to the growth inhibitory effect of PD. Small interfering RNA against p16 significantly increased the sensitivity of KP-MRT-YM cells to PD (p < 0.05). These results suggest that p16 expression in MRT could be used to predict its sensitivity to PD. PD may be an attractive agent for patients with MRT whose tumors express low levels of p16. |
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Keywords: | Abbreviations: MRT malignant rhabdoid tumor INI1 integrase interactor 1 CDK4 cyclin-dependent kinase 4 PD PD 0332991 siRNA small interfering RNA PCNA proliferating cell nuclear antigen GAPDH glucose-6-phosphate dehydrogenase |
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