期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 2, 页码 259-266出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm801195k
关键词
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资金
- MIUR [FIRB 2001, PRIN-2005034305_001, PRIN-20078J9L2A_005]
- Universities of Bologna, Genova, and Napoli
The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c]-[1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC50 reduction >= 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its anti proliferative activity in multidrug resistant A2780/DX3 cells.
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