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


CONCLUSIONS
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.
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Indira
I
Benakanakere
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Tyler
T
Johnson
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Richard
R
Sleightholm
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Virgilio
V
Villeda
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Monika
M
Arya
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA.
Ravi
R
Bobba
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA ; Cancer Center, Saint Louis University, Saint Louis, MO 63110, USA ; 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.
Carl
C
Freter
Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of Missouri, Columbia, MO 65212, USA ; Cancer Center, Saint Louis University, Saint Louis, MO 63110, USA ; 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.
Chunfa
C
Huang
Cholesterol lowering agent; Chronic lymphocytic leukemia; Fludarabine; Rituximab