Polyphenols enhance the activity of alkylating agents in leukaemia cell lines.

Polyphenols have been shown to sensitize solid tumours to alkylating agents such as cisplatin, and induce apoptosis and/or cell-cycle arrest. Here, we assess the effects of five polyphenols alone and in combination with three alkylating agents: cisplatin, cyclophosphamide and chlorambucil in lymphoid and myeloid leukaemia cells lines, and non-tumour control cells. In lymphoid leukaemia cell lines there was a synergistic reduction in ATP and glutathione levels, an induction of cell cycle arrest, DNA damage and apoptosis when quercetin, apigenin, emodin and rhein were combined with cisplatin and cyclophosphamide; and when apigenin and rhein were combined with chlorambucil. In myeloid leukaemia cells quercetin, apigenin and emodin showed a similar synergistic effect with all alkylating agents; however antagonistic effects were observed with some or all alkylating agents when combined with emodin, rhein and cis-stilbene. All synergistic effects were associated with reduced glutathione levels, DNA damage and apoptosis; whilst during antagonism the reverse effects were observed. The combination of alkylating agents, particularly cisplatin with polyphenols could be promising for the treatment of lymphoid leukaemias, with apigenin showing the greatest effects. Likewise in myeloid cells apigenin also synergised the action of all alkylating agents, suggesting that apigenin may also be beneficial in myeloid leukaemias.