Abstract:
:Phospholipidosis is the excessive accumulation of intracellular phospholipids in cell lysosomes. Drugs that induce this disease often share common physiochemical properties and are collectively classified as cationic amphiphilic drugs (CADs). Although the cause of phospholipidosis and morphologic appearance of affected lysosomes have been studied extensively, less is known about the physiologic effects of the condition. In the current study, U-937 cells were incubated with the CADs amiodarone (2.5-10 microg/mL) and imipramine (2.5-20 microg/mL). Treatment of U-937 cells with these compounds for 96 h resulted in concentration-related increases in phospholipids, as assessed by flow cytometry using the fluorophore nile red. These results were verified by measuring the concentrations of choline-derived phospholipids, which were significantly increased in drug-treated cells. Cell number in amiodarone (10 microg/mL) and imipramine (20 microg/mL) cultures following the 96-h incubation period were markedly reduced compared to control cultures. These observations suggested that accumulation of cellular phospholipids could inhibit cell proliferation. Flow cytometric analysis revealed a decrease in the percentage of cells in the S-phase of the cell cycle following drug treatment, yet DNA replication still occurred in a significant portion of cells. Interestingly, amiodarone and imipramine induced apoptosis in U-937 cells as shown by annexin V-FITC staining and DNA fragmentation. Enzymatic assays demonstrated that amiodarone and imipramine induced the activity of caspases 2 and 3. These results suggest that disruption of cell lysosomes in U-937 cells following accumulation of phospholipids does not cause a cell cycle arrest but instead induces apoptosis by activation of caspase pathways.
journal_name
Drug Chem Toxicoljournal_title
Drug and chemical toxicologyauthors
Piccotti JR,LaGattuta MS,Knight SA,Gonzales AJ,Bleavins MRdoi
10.1081/dct-39743subject
Has Abstractpub_date
2005-01-01 00:00:00pages
117-33issue
1eissn
0148-0545issn
1525-6014journal_volume
28pub_type
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