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Published on: May 15, 2019
Erucylphospho-N,N,N-trimethylpropylammonium shows substantial cytotoxicity in multiple myeloma cells
Deyan Y Yosifov1, Spiro M Konstantinov, Martin R Berger
1Department of Pharmacology, Laboratory for Experimental Chemotherapy, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria. deyanyosifov@abv.bg
Abstract:
Multiple myeloma (MM) is a frequent hematological malignancy that is incurable despite recent developments, such as proteasome and angiogenic inhibitors. Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is an i.v. injectable alkylphosphocholine with antineoplastic activity based on an unusual mode of action and is currently undergoing clinical trials in leukemia patients. The aim of this investigation was to evaluate the efficacy of erufosine in MM cells and to study the modulation of cell-death pathways. The cytotoxicity of erufosine against three MM cell lines (RPMI-8226, U-266, and OPM-2) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-dye reduction assay. All MM cell lines responded to erufosine, RPMI-8226 cells being most and U-266 being least sensitive. The respective IC(50) values were 3.2 and 16.2 micromol/L. Various cell-death characteristics were studied in response to erufosine, such as morphological changes, oligonucleosomal DNA fragmentation, caspase activation, and poly (ADP)-ribose polymerase cleavage. Erufosine was found to cause cell shrinkage, chromatin condensation, and caspase-8 and -3 activation. Taken together, our data indicate that erufosine is a potential antimyeloma drug eliciting specific features of apoptotic cell death in vitro.
Insights
Erufosine, an alkylphosphocholine, shows efficacy against multiple myeloma (MM) cells by inducing apoptosis. This novel drug demonstrates potential as an antimyeloma therapeutic, warranting further investigation in clinical trials.
Area of Science:
- Oncology
- Pharmacology
Background:
- Multiple myeloma (MM) is a prevalent, incurable hematological malignancy.
- Current treatments include proteasome and angiogenic inhibitors, but novel therapies are needed.
Purpose of the Study:
- To evaluate the efficacy of erucylphospho-N,N,N-trimethylpropylammonium (erufosine) in multiple myeloma cells.
- To investigate the mechanisms of cell-death pathways modulated by erufosine.
Main Methods:
- Cytotoxicity was assessed using the MTT assay on three MM cell lines (RPMI-8226, U-266, OPM-2).
- Morphological changes, DNA fragmentation, caspase activation, and PARP cleavage were analyzed.
Main Results:
- Erufosine exhibited cytotoxicity against all tested MM cell lines, with IC(50) values ranging from 3.2 to 16.2 micromol/L.
- The drug induced characteristic apoptotic features, including cell shrinkage, chromatin condensation, and activation of caspase-8 and caspase-3.
Conclusions:
- Erufosine demonstrates significant antimyeloma activity in vitro.
- The drug effectively triggers apoptotic cell death pathways in multiple myeloma cells, suggesting its potential as a therapeutic agent.
