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Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin
L Maksumova1, K Ohnishi, F Muratkhodjaev
1Department of Medicine III, Hamamatsu University School of Medicine, Japan.
Abstract:
Lovastatin, a competitive inhibitor of HMG-CoA reductase, reportedly inhibits proliferation and induces apoptosis of tumor cells with MDR-1 coded P-glycoprotein (Pgp) expression. In this study we investigated the sensitivity to lovastatin of eight myeloid leukemia cell lines: K562, NOMO-1, NB4 and its retinoic acid (RA) resistant subline NB4/RA, and their multidrug-resistant (MDR) sublines: K562/ADR, NOMO-1/ADR, NB4/MDR and NB4/RA/MDR. MTT and apoptosis assays revealed that K562/ADR, NOMO-1/ADR and NB4/RA/MDR were more sensitive to lovastatin than their parental cell lines, while NB4/MDR showed the same level of sensitivity as parental NB4 cells, which already were very sensitive to lovastatin. Significant elevation of transcript levels of HMG-CoA reductase was observed by semiquantitative RT-PCR analysis in more than three lovastatin-sensitive MDR sublines, but not in NB4/MDR compared with the parental cell lines. HMG-CoA reductase mRNA levels were up-regulated more than two-fold by the exposure to lovastatin in all of the parental non-Pgp-expressing cell lines. In NB4/MDR, HMG-CoA reductase mRNA level was elevated to a similar extent as in parental NB4, whereas in three other MDR sublines which showed preferential sensitivity to lovastatin, their HMG-CoA reductase mRNA levels were not significantly elevated after 24- and 48-h treatment with lovastatin. These results indicate a connection between drug resistance and regulation of the mevalonate pathway, and further strengthen the clinical possibility that drug resistant leukemias would be susceptible to treatment with lovastatin.
Insights
Lovastatin shows promise for treating drug-resistant myeloid leukemias. Certain multidrug-resistant (MDR) leukemia cells are more sensitive to lovastatin, suggesting a link between drug resistance and the mevalonate pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Lovastatin inhibits HMG-CoA reductase, impacting tumor cell proliferation and apoptosis.
- Multidrug resistance (MDR) in cancer, often mediated by P-glycoprotein (Pgp), poses a significant therapeutic challenge.
- Understanding lovastatin's efficacy in MDR cancer cells is crucial for developing new treatment strategies.
Purpose of the Study:
- To investigate the sensitivity of various myeloid leukemia cell lines, including multidrug-resistant (MDR) sublines, to lovastatin.
- To explore the relationship between lovastatin sensitivity, P-glycoprotein expression, and HMG-CoA reductase regulation in these cell lines.
Main Methods:
- Utilized MTT and apoptosis assays to assess lovastatin sensitivity in eight myeloid leukemia cell lines and their MDR sublines.
- Employed semiquantitative reverse transcription polymerase chain reaction (RT-PCR) to analyze HMG-CoA reductase transcript levels.
- Examined the impact of lovastatin treatment on HMG-CoA reductase mRNA expression in both parental and MDR cell lines.
Main Results:
- K562/ADR, NOMO-1/ADR, and NB4/RA/MDR sublines exhibited increased sensitivity to lovastatin compared to their parental counterparts.
- NB4/MDR cells displayed similar lovastatin sensitivity as the highly sensitive parental NB4 cells.
- HMG-CoA reductase transcript levels were significantly elevated in sensitive MDR sublines, but not in NB4/MDR, suggesting a complex regulatory mechanism.
Conclusions:
- A correlation exists between drug resistance mechanisms in leukemia and the regulation of the mevalonate pathway.
- Lovastatin demonstrates potential as a therapeutic agent for drug-resistant leukemias.
- Further research into lovastatin's effects on MDR cancer cells is warranted to optimize clinical applications.