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Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells.

Benakanakere I, Johnson T, Sleightholm R, Villeda V, Arya M, Bobba R, Freter C, Huang C - Exp Hematol Oncol (2014)

Bottom Line: We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression.More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients.These results provide a novel strategy which could be applied to CLL treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.

ABSTRACT

Background: Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL).

Methods: MEC-2 cells, a CLL cell line, and the peripheral blood mononuclear cells (PBMCs) from CLL patients were treated with cholesterol lowering agents, and analyzed the effect of these agents on cholesterol levels, CD-20 expression and distribution, and cell viability in the presence or absence of fludarabine, rituximab or their combinations.

Results: We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression. Furthermore, treatment of cells with fludarabine, rituximab or their combinations in the presence of BIBB-515, YM-53601 or TAK-475 enhanced MEC-2 cell chemoimmuno-sensitivity measured by cell viability. More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients.

Conclusion: Our data demonstrate that BIBB-515, YM53601 and TAK-475 render chemoimmuno-therapy resistant MEC-2 cells sensitive to chemoimmuno-therapy and enhance CLL cell chemoimmuno-sensitivity without CD-20 epitope presentation or its downstream signaling. These results provide a novel strategy which could be applied to CLL treatment.

No MeSH data available.


Related in: MedlinePlus

Lovastatin lowers cellular cholesterol and enhances chemo-sensitivity. A) MEC-2 cells were treated with 5 μM lovastatin (L) for 3 days, the samples were extracted and analyzed for total cellular cholesterol (n = 5). C, control (no lovastatin). B) MEC-2 cells were treated with 10 μM fludarabine (F), 10 μg/ml rituximab (R) or their combinations (F + R) in the presence or absence of 5 μM lovastatin for 3 days, and analyzed cell viability by MTT assay (n = 16). The values of lovastatin treatment were statistically different from the controls. *P < 0.05. **P < 0.01.
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Figure 3: Lovastatin lowers cellular cholesterol and enhances chemo-sensitivity. A) MEC-2 cells were treated with 5 μM lovastatin (L) for 3 days, the samples were extracted and analyzed for total cellular cholesterol (n = 5). C, control (no lovastatin). B) MEC-2 cells were treated with 10 μM fludarabine (F), 10 μg/ml rituximab (R) or their combinations (F + R) in the presence or absence of 5 μM lovastatin for 3 days, and analyzed cell viability by MTT assay (n = 16). The values of lovastatin treatment were statistically different from the controls. *P < 0.05. **P < 0.01.

Mentions: Earlier studies indicated that cholesterol biosynthesis (Figure 2) is mandatory for cellular growth and has been implicated in various aspects of tumor development and progression[33-35]. Certain classes of drugs, such as statins, inhibit mevalonate metabolism and exhibit growth inhibitory and pro-apoptotic properties as well as antitumor activity[27-29,36]. Next, we tested the effect of lovastatin on cholesterol metabolism and cell viability in chemoimmuno-therapeutic drug-treated MEC-2 cells. Figure 3A shows that incubation with 5 μM lovastatin for 3 days reduced cellular cholesterol levels by 30%. In cell treated with lovastatin, fludarabine and lovastatin plus fludarabine, cell viability was 75, 80, and 57% of control, respectively. However, lovastatin had little effect in the cells treated with rituximab alone (Figure 3B, middle panel). The results indicate that lovastatin may interfere with CD-20 and rituximab-mediated activity. One recent report showed that statins induce conformational changes of CD20 and impair rituximab-mediated complement-dependent cytotoxicity[32], consistent with our findings.


Targeting cholesterol synthesis increases chemoimmuno-sensitivity in chronic lymphocytic leukemia cells.

Benakanakere I, Johnson T, Sleightholm R, Villeda V, Arya M, Bobba R, Freter C, Huang C - Exp Hematol Oncol (2014)

Lovastatin lowers cellular cholesterol and enhances chemo-sensitivity. A) MEC-2 cells were treated with 5 μM lovastatin (L) for 3 days, the samples were extracted and analyzed for total cellular cholesterol (n = 5). C, control (no lovastatin). B) MEC-2 cells were treated with 10 μM fludarabine (F), 10 μg/ml rituximab (R) or their combinations (F + R) in the presence or absence of 5 μM lovastatin for 3 days, and analyzed cell viability by MTT assay (n = 16). The values of lovastatin treatment were statistically different from the controls. *P < 0.05. **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4231203&req=5

Figure 3: Lovastatin lowers cellular cholesterol and enhances chemo-sensitivity. A) MEC-2 cells were treated with 5 μM lovastatin (L) for 3 days, the samples were extracted and analyzed for total cellular cholesterol (n = 5). C, control (no lovastatin). B) MEC-2 cells were treated with 10 μM fludarabine (F), 10 μg/ml rituximab (R) or their combinations (F + R) in the presence or absence of 5 μM lovastatin for 3 days, and analyzed cell viability by MTT assay (n = 16). The values of lovastatin treatment were statistically different from the controls. *P < 0.05. **P < 0.01.
Mentions: Earlier studies indicated that cholesterol biosynthesis (Figure 2) is mandatory for cellular growth and has been implicated in various aspects of tumor development and progression[33-35]. Certain classes of drugs, such as statins, inhibit mevalonate metabolism and exhibit growth inhibitory and pro-apoptotic properties as well as antitumor activity[27-29,36]. Next, we tested the effect of lovastatin on cholesterol metabolism and cell viability in chemoimmuno-therapeutic drug-treated MEC-2 cells. Figure 3A shows that incubation with 5 μM lovastatin for 3 days reduced cellular cholesterol levels by 30%. In cell treated with lovastatin, fludarabine and lovastatin plus fludarabine, cell viability was 75, 80, and 57% of control, respectively. However, lovastatin had little effect in the cells treated with rituximab alone (Figure 3B, middle panel). The results indicate that lovastatin may interfere with CD-20 and rituximab-mediated activity. One recent report showed that statins induce conformational changes of CD20 and impair rituximab-mediated complement-dependent cytotoxicity[32], consistent with our findings.

Bottom Line: We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression.More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients.These results provide a novel strategy which could be applied to CLL treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.

ABSTRACT

Background: Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. Statins, cholesterol lowering drugs, can induce apoptosis, but also negatively interfere with CD-20 and rituximab-mediated activity. Our goal is to identify the alternative targets that could reduce cholesterol levels but do not interfere with CD-20 in chemo immunotherapy of chronic lymphocytic leukemia (CLL).

Methods: MEC-2 cells, a CLL cell line, and the peripheral blood mononuclear cells (PBMCs) from CLL patients were treated with cholesterol lowering agents, and analyzed the effect of these agents on cholesterol levels, CD-20 expression and distribution, and cell viability in the presence or absence of fludarabine, rituximab or their combinations.

Results: We found that MEC-2 cells treated with cholesterol lowering agents (BIBB-515, YM-53601 or TAK-475) reduced 20% of total cellular cholesterol levels, but also significantly promoted CD-20 surface expression. Furthermore, treatment of cells with fludarabine, rituximab or their combinations in the presence of BIBB-515, YM-53601 or TAK-475 enhanced MEC-2 cell chemoimmuno-sensitivity measured by cell viability. More importantly, these cholesterol lowering agents also significantly enhanced chemoimmuno-sensitivity of the PBMCs from CLL patients.

Conclusion: Our data demonstrate that BIBB-515, YM53601 and TAK-475 render chemoimmuno-therapy resistant MEC-2 cells sensitive to chemoimmuno-therapy and enhance CLL cell chemoimmuno-sensitivity without CD-20 epitope presentation or its downstream signaling. These results provide a novel strategy which could be applied to CLL treatment.

No MeSH data available.


Related in: MedlinePlus