Oncotarget

Research Papers:

CK2 and PI3K are direct molecular targets of quercetin in chronic lymphocytic leukaemia

Maria Russo, Alfonsina Milito, Carmela Spagnuolo, Virginia Carbone, Anders Rosén, Paola Minasi, Fabio Lauria and Gian Luigi Russo _

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Oncotarget. 2017; 8:42571-42587. https://doi.org/10.18632/oncotarget.17246

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Abstract

Maria Russo1, Alfonsina Milito1,3, Carmela Spagnuolo1, Virginia Carbone1, Anders Rosén2, Paola Minasi1, Fabio Lauria1 and Gian Luigi Russo1

1Institute of Food Sciences, National Research Council, Avellino, Italy

2Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden

3Current address: Stazione Zoologica “Anton Dohrn”, Villa Comunale, Napoli, Italy

Correspondence to:

Gian Luigi Russo, email: glrusso@isa.cnr.it

Keywords: quercetin, protein kinase CK2, PI3K, chronic lymphocytic leukaemia, Mcl-1

Received: January 10, 2017     Accepted: April 05, 2017     Published: April 19, 2017

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.


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