Research Papers:

Dietary polyphenols influence antimetabolite agents: methotrexate, 6-mercaptopurine and 5-fluorouracil in leukemia cell lines

Amani Mahbub, Christine Le Maitre, Sarah Haywood-Small, Neil Cross and Nicola Jordan-Mahy _

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Oncotarget. 2017; 8:104877-104893. https://doi.org/10.18632/oncotarget.20501

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Amani Mahbub1, Christine Le Maitre2, Sarah Haywood-Small2, Neil Cross2 and Nicola Jordan-Mahy2

1Laboratory Medicine College, Pathology Department, Umm Al Qura University, Makkah, Saudi Arabia

2Biomolecular Sciences Research Center, Sheffield Hallam University, Sheffield, UK

Correspondence to:

Nicola Jordan-Mahy, email: [email protected]

Keywords: leukemia; 6-mercaptopurine; polyphenols; methotrexate; 5-fluorouracil

Received: November 22, 2016    Accepted: August 04, 2017    Published: August 24, 2017


Polyphenols have been previously shown to sensitize leukemia cell lines to topoisomerase inhibitors. Here, we assess the effects of five polyphenols when used alone and in combination with antimetabolites: methotrexate, 6-mercaptopurine and 5-fluorouracil; in lymphoid and myeloid leukemia cells lines, and non-tumor control cells. The effects of combined treatments were investigated on ATP and glutathione levels, cell-cycle progression, DNA damage and apoptosis.

Polyphenols antagonized methotrexate and 6-mercaptopurine induced cell-cycle arrest and apoptosis in most leukemia cell lines. This was associated with reduced DNA damage and increased glutathione levels, greater than that seen following individual treatments alone.

In contrast, 5-fluorouracil when combined with quercetin, apigenin and rhein caused synergistic decrease in ATP levels, induction of cell-cycle arrest and apoptosis in some leukemia cell lines. However, antagonistic effects were observed when 5-fluorouracil was combined with rhein and cis-stilbene in myeloid cell lines. The effects were dependant on polyphenol type and chemotherapy agent investigated, and cell type treated. Interestingly treatment of non-tumor control cells with polyphenols protected cells from antimetabolite treatments.

This suggests that polyphenols modulate the action of antimetabolite agents; more importantly they antagonized methotrexate and 6-mercaptopurine actions, thus suggesting the requirement of polyphenol-exclusion during their use.

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