Abstract
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.
Highlights
The mortality of leukemia is still high despite considerable improvements in tolerance and efficacy of chemotherapeutic agents [1]
Methotrexate is used in the treatment of all types of leukemia; and commonly used in the treatment of childhood acute lymphoid leukemia [1, 4,5,6]. 6-Mercaptopurine is approved for acute lymphocytic leukemia, childhood acute lymphoid leukemia, as well as acute and chronic myeloid leukemia [1, 4,5]; whilst, 5-fluorouracil is used primarily in the treatment of acute myeloid leukemia [7,8]
The lowest significant dose (LSD) for caspase-3 activity were found to be the same or slightly higher than the LSDs for ATP levels, as a reflection of the progression from a reduction of cell viability to early stage apoptosis (Table 1). These LSDs were used to investigate the effects of combination treatments and establish whether polyphenols have synergistic or antagonistic effects on antimetabolite agents
Summary
The mortality of leukemia is still high despite considerable improvements in tolerance and efficacy of chemotherapeutic agents [1] Antimetabolite agents such as methotrexate, 6-mercaptopurine and 5-fluorouracil are some of the most commonly used chemotherapy agents used to treat leukemia [1]. 6-Mercaptopurine is approved for acute lymphocytic leukemia, childhood acute lymphoid leukemia, as well as acute and chronic myeloid leukemia [1, 4,5]; whilst, 5-fluorouracil is used primarily in the treatment of acute myeloid leukemia [7,8]. These antimetabolites are non-specific, affecting both normal and malignant cells. These drugs are associated with severe side-effects and drug resistance [1,2,3,4,5, 9]
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