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

Experimental Hematology & Oncology

Chunfa Huang¹  Carl Freter¹  Ravi Bobba²  Monika Arya²  Virgilio Villeda²  Richard Sleightholm²  Tyler Johnson²  Indira Benakanakere² 

[1] Division of Hematology/Oncology, Department of Internal Medicine School of Medicine, and Cancer Center, Saint Louis University, 3655 Vista Avenue, St. Louis, MO 63110-2539, USA;Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA

关键词: Chronic lymphocytic leukemia;    Cholesterol lowering agent;    Rituximab;    Fludarabine;   

Others  :  1135302
DOI  :  10.1186/2162-3619-3-24

 received in 2014-07-28, accepted in 2014-09-14,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Benakanakere et al.; licensee BioMed Central Ltd.

【 图 表 】

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