Identification of the phenothiazine-derived drug targeting the KRAS-mutant cells in non-small cell lung cancer
| Autor: | Meng-Hua Lee, 李孟樺 |
|---|---|
| Rok vydání: | 2015 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 103 Thioridazine is a class of anti-psychotic drug called phenothiazine for the treatment of schizophrenia. Recently, we and others have shown that thioridazine is a cancer stem cell (CSC) inhibitor. However, the molecular mechanism of thioridazine in anti-CSC effect has not been elucidated. Interestingly, thioridazine has R and S two enantiomes. In this study, we hypothesized that these two enantiomers (referred to as T1 and T2) of thioridazine might inhibit the lung cancer cells with distinct efficacy and through different mechanisms. Here, we employed the L1000 microarray to explore the differentially gene expression profiles and to compare pathways of thioridazine enantiomers. Using these gene expression signatures, the putative targets of thioridazine were predicted through a LINCS system, which contains ~1,320,000 L1000 profiles. The prioritized pathways affected by thioridazine are predicted to be AMPK and cholesterol-biosynthesis pathways. Consistent with the prediction, the colony formation of lung cancer cells was inhibited by thioridazine through disrupting cholesterol-biosynthesis pathway. Moreover, the cholesterol biosynthesis was also interfered by thioridazine and resulted in the stemness inhibition and cell viability reduction in lung cancer stem cells. More importantly, one of the enantiomers, T2, has better inhibitory effect on KRAS mutant cells than T1. Finally, the in vivo tumor suppressive effect of T2 and Alimta combined treatment groups appeared to be the most significant in H441 (KRAS mutant)-bearing mice. Taken together, thioridazine-T2 may have therapeutic benefits on anti-CSCs for NSCLC as compared to T1 on KRAS mutant lung cancer cells. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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