Abstract
Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients. To identify the molecular target of quercetin, we employed a new cell line, HG3, obtained by immortalization of B-cells from a chronic lymphocytic leukaemia patient at the later stage of disease. We confirmed that quercetin in association with ABT-737 synergistically enhances apoptosis in HG3 (combination index < 1 for all fractions affected). We also reported that the cellular uptake of quercetin is extremely rapid, with an intracellular concentration of about 38.5 ng/106 cells, after treatment with 25 μM for 5 min. We demonstrated that the activity of protein kinase CK2, which positively triggers PI3K/Akt pathway by inactivating PTEN phosphatase, is inhibited by quercetin immediately after its addition to HG3 cells (0–2 min). PI3K activity was also inhibited by quercetin within 60 min from the treatment. The combined inhibition of CK2 and PI3K kinase activities by quercetin restored ABT-737 sensitivity and increased lethality in human leukemia cells.
Highlights
According with the recently published statistics on cancer in USA, B cell-chronic lymphocytic leukemia (CLL) remains the most common form of adult leukemia in the Western world, with 18,960 new cases expected in 2016 and 4,660 estimated death [1]
Both markers are highly expressed in Ig heavy chain variable region (IGHV)-UM CLL and their overexpression is associated with poor diagnosis and shorter time to treatment and survival, the correlation with the aggressiveness of the disease and resistance to therapy is more pronounced for CLL expressing Zap-70, than for those with high level of CD38 whose expression vary over time [8, 9]
We previously demonstrated that quercetin is able to restore sensitivity to apoptosis in leukemic cell lines and B-cells from CLL patients when associated with ABT737 [31]
Summary
According with the recently published statistics on cancer in USA, B cell-chronic lymphocytic leukemia (CLL) remains the most common form of adult leukemia in the Western world, with 18,960 new cases expected in 2016 and 4,660 estimated death [1]. The origin of B-CLL is still controversial, recent evidence suggest that genetic and epigenetic alterations occurring in pluripotent haematopoietic stem cells (HSCs) in the earliest phase of B lymphocytes may possibly lead to CLL [2, 4] According to this model, antigenic stimulation of CLL HSCs may lead to selection and expansion of mature B cells, with the generation of oligoclonal populations. The tyrosine kinase Zap is involved in T-cell receptor signaling and regulation, while CD38 is a surface antigen Both markers are highly expressed in IGHV-UM CLL and their overexpression is associated with poor diagnosis and shorter time to treatment and survival, the correlation with the aggressiveness of the disease and resistance to therapy is more pronounced for CLL expressing Zap-70, than for those with high level of CD38 whose expression vary over time [8, 9]
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