Abstract

Background

Polyphenols have been shown to sensitize cancer cells from solid tumours to some alkylating agents such as cisplatin and induce apoptosis and/or cell-cycle arrest. This sensitization could enable a reduction of alkylating agent dose and decrease off-target side effects; whilst still maintaining treatment efficacy. However, actions in leukaemia cells have not been previously determined.

Method

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. The effects of combined treatments were investigated on ATP levels, glutathione levels, cell-cycle progression, DNA damage and apoptosis.

Results

In lymphoid leukaemia cell lines, quercetin, apigenin, emodin and rhein synergistically enhanced cisplatin and cyclophosphamide activity, reducing ATP and glutathione levels, causing cell-cycle arrest, DNA damage and apoptosis. Similarly, apigenin and rhein acted synergistically when combined with chlorambucil in lymphoid leukaemia cell lines. In myeloid leukaemia cell lines, all three alkylating agents had differential effects. Synergistic effects were observed when alkylating agents were combined with quercetin, apigenin and emodin; whilst antagonistic effects were observed with some or all alkylating agents when combined with emodin, rhein and cis-stilbene. The observed synergistic effects were associated with a decrease in glutathione levels, DNA damage and apoptosis; whilst during antagonism the contrary effect was observed, glutathione levels were increased, and DNA damage was reduced.

Conclusion

In conclusion, this study suggests that combination of alkylating agents, in particular cisplatin with polyphenols could be promising for the treatment of lymphoid leukaemias, with apigenin showing the greatest synergistic effects with all alkylating agents. However, emodin, rhein and cis-stilbene were shown to antagonise the alkylating agent in myeloid leukaemia cell line. However, the use of apigenin with all alkylating agents could prove beneficial for myeloid leukaemia patients.