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Resistance to the new anti-cancer phospholipid ilmofosine (BM 41 440)
1Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Abstract:
The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase II clinical trials. Because resistance to anti-tumour drugs is a major problem in cancer treatment, we investigated the resistance of different cell lines to this compound. Here we report that the multidrug-resistant cell lines MCF7/ADR, CCRFNCR1000, CCRF/ADR500, CEM/VLB100 and HeLa cell lines transfected with a wild-type and mutated (gly/val185) multidrug resistance 1 gene (MDR1) are cross-resistant to ilmofosine compared with the sensitive parental cell lines. In CEMNM-1 cells, in which the resistance is associated with an altered topoisomerase II gene, no cross-resistance to ilmofosine was observed. Ilmofosine is not capable of modulating multidrug resistance and neither does it reduce the labelling of the P-glycoprotein (P-gp) by azidopine nor alter ATPase activity significantly. The resistance to ilmofosine in multidrug-resistant CCRF/VCR1000 cells cannot be reversed by the potent multidrug resistance modifier dexniguldipine-HCI (B8509-035). A tenfold excess of ilmofosine does not prevent the MDR-modulating effect of dexniguldipine-HCl. Treatment of cells with ilmofosine does not alter the levels of MDR1 mRNA. Long-term treatment of an ilmofosine-resistant Meth A subline with the drug does not induce multidrug resistance, indicating that ilmofosine does not increase the level of P-gp. Determination of the MDR2 mRNA levels in the cells revealed that the resistance pattern to ilmofosine is not correlated with the expression of this gene. It is concluded, therefore, that multidrug-resistant cells are cross-resistant to ilmofosine and that the compound is not a substrate of Pgp. No association between the expression of the MDR2-encoded P-gp and resistance to ilmofosine was observed. It is supposed that MDR1-associated alterations in membrane lipids cause resistance to ilmofosine.
Insights
Multidrug-resistant cancer cells show cross-resistance to the anti-cancer drug ilmofosine, suggesting it is not a substrate of P-glycoprotein (P-gp). This resistance may stem from MDR1 gene-associated alterations in membrane lipids.
Area of Science:
- Oncology
- Molecular Biology
- Drug Resistance Mechanisms
Background:
- Ilmofosine (BM 41 440) is a novel thioether phospholipid anti-cancer agent in Phase II clinical trials.
- Drug resistance is a significant challenge in cancer therapy, necessitating investigation into resistance mechanisms of new drugs.
Purpose of the Study:
- To investigate the cross-resistance patterns of various multidrug-resistant (MDR) cell lines to ilmofosine.
- To determine if ilmofosine is a substrate of P-glycoprotein (P-gp) or modulates MDR1 gene expression.
Main Methods:
- Testing ilmofosine sensitivity in MDR cell lines (MCF7/ADR, CCRFNCR1000, etc.) and their sensitive parental counterparts.
- Assessing ilmofosine's effect on P-gp labeling, ATPase activity, MDR1 mRNA levels, and resistance reversal by dexniguldipine-HCl.
- Evaluating resistance in cells with altered topoisomerase II and MDR2 gene expression.
Main Results:
- Multiple MDR cell lines, including those transfected with MDR1 gene, exhibited cross-resistance to ilmofosine.
- CEMNM-1 cells with altered topoisomerase II showed no cross-resistance.
- Ilmofosine did not modulate P-gp activity, reduce P-gp labeling, or alter MDR1 mRNA levels.
- Resistance to ilmofosine was not reversed by dexniguldipine-HCl and was not correlated with MDR2 gene expression.
Conclusions:
- Multidrug-resistant cells are cross-resistant to ilmofosine.
- Ilmofosine is not a substrate of P-gp, and its resistance is not mediated by MDR1 or MDR2 gene expression.
- MDR1-associated alterations in membrane lipids are hypothesized to cause resistance to ilmofosine.