In vitro cell signalling modulation using combination of doxorubicin with baicalein in myeloid leukaemia – preliminary study [Presentation]

A rising problem in developed countries associated with age are haematological cancers, including acute (AML) and chronic myeloid leukaemia (CML). The exact cause of myeloid leukaemia remains unknown, but leukaemogenesis is promoted by aberrant cell signalling in pathways such as apoptosis and autophagy which leads to increased cellular proliferation and leukaemic cell survival. The anthracycline doxorubicin (Dox) is an established chemotherapy for myeloid leukaemia with the caveat of adverse side effects for the patients. The flavone baicalein, which is a plant extract, has shown promising anticancer properties with no severe side effects and favourable safety.

Preliminary in vitro studies in the cell lines K562 (CML), MOLM-13 (AML) and U937 (histiocytic lymphoma, monocytic myeloid cells) aimed to determine the effective concentrations of baicalein and Dox for further drug combination studies. Cytotoxicity assays have been optimised using CyQuant GR after 2-day treatment of cells with varying concentrations of Dox or baicalein. Dox treatments (0.039 μM - 2.5 μM) presented dose-dependent inverse relationship with viability in all tested cell lines. MOLM-13 presented with the highest sensitivity towards Dox (7-fold difference) with significantly lower IC50 (=0.034 μM; p=0.006) compared to K562 (IC50=0.239 μM). For baicalein (1.25 μM - 80 μM), a dose-dependent cytotoxicity was observed if [baicalein]>10 μM with K562 (IC50=22.4 μM) and MOLM-13 (IC50=18.5 μM) presenting similar sensitivity. However, lower sensitivity to baicalein was observed in U937 (IC50=39.3 μM; p<0.0001 compared to the other two cell lines).

These findings show promising first steps for further studies into the drug combination development using various flavones in structure-related activities. Human samples will be obtained to further validate the findings. Future work will also focus on targeting established biomarkers and elucidating mechanism of action of the drug combinations at protein, genetic and epigenetic level in cell signalling pathways such as apoptosis, autophagy, Wnt.