Abstract
BackgroundCholesterol 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).MethodsMEC-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.ResultsWe 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.ConclusionOur 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.
Highlights
Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity
Effect of chemoimmuno-therapeutic drugs in MEC-2 cell viability and apoptosis To investigate whether chemoimmuno-sensitivity of chronic lymphocytic leukemia (CLL) cells could be altered, we chose MEC-2 cells, a fludarabine- and rituximab-insensitive CLL cell line
These results demonstrate that chemo- or immunotherapeutic drugs induce MEC-2 apoptosis
Summary
Cholesterol plays an important role in cancer development, drug resistance and chemoimmuno-sensitivity. 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). Fludarabine, are effective agents to treat CLL, resulting in a higher complete response rate than chlorambucil or alkylating-based chemotherapies (20-30% versus 10%) and a longer diseasefree interval; survival, is not prolonged [10]. Rituximab and alemtuzumab result in a higher complete response rate than chlorambucil in chemonaïve patients [11,12]. The combination of fludarabine, cyclophosphamide and rituximab treatment achieves complete responses in only 24% to 39% of patients [15,16]. It is clear that new approaches to overcoming drug-resistance and potentiating the action of conventional therapy are urgently needed
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