Abstract
5-Fluorouracil (FU) is a halogenated nucleobase analog that is widely used in chemotherapy. Here we show that 5-hydroxymethyl-2'-deoxyuridine (hmUdR) synergistically enhances the activity of FU in cell lines derived from solid tumors but not normal tissues. While the cytotoxicity of FU and hmUdR was not directly related to the amount of the modified bases incorporated into cellular DNA, incubation with this combination resulted in dramatic increase in the number of single strand breaks in replicating cancer cells, leading to NAD-depletion as consequence of poly(ADP-ribose) synthesis and S phase arrest. Cell death resulting from the base/nucleoside combination did not occur by apoptosis, autophagy or necroptosis. Instead, the cells die via necrosis as a result of NAD depletion. The FU-related nucleoside analog, 5-fluoro-2'-deoxyuridine, also displayed synergy with hmUdR, whereas hmUdR could not be replaced by 5-hydroxymethyluracil. Among other 5-modified deoxyuridine analogs tested, 5-formyl-2'-deoxyuridine and, to a lesser extent, 5-hydroxy-2'-deoxyuridine, also acted synergistically with FU, whereas 5-hydroxyethyl-2'-deoxyuridine did not. Together, our results have revealed an unexpected synergistic interaction between deoxyuridine analogs and FU in a cancer cell-specific manner, and suggest that these novel base/nucleoside combinations could be developed into improved FU-based chemotherapies.
Highlights
Since its first rational development in 1957, 5-fluorouracil (FU) has been widely used as a chemotherapy reagent for various types of cancers, including colorectal, breast and pancreatic cancers [1]
We report the novel and unexpected observation that the deoxyuridine analogs, hmUdR, hUdR and foUdR, synergistically enhance the sensitivity of a variety of cell lines derived from solid tumors but not cell lines from normal tissues to FU
While our results do not exclude the possibility that the combination of FU and the deoxyuridine analogs synergistically inhibit RNA metabolism, the dramatic increase in DNA single strand breaks indicates that the combination of FU with one of the active deoxyuridine analogs is synergistically impacting the integrity of genomic DNA
Summary
Since its first rational development in 1957, 5-fluorouracil (FU) has been widely used as a chemotherapy reagent for various types of cancers, including colorectal, breast and pancreatic cancers [1]. The mechanism of action of FU has been studied extensively, and a number of derivatives and combination therapies with other types of therapeutics have been developed to improve its effectiveness [2]. These combination therapies often increase the risk of severe side effects limiting clinical application, and many tumor types exhibit a low response rate and/or www.impactjournals.com/oncoscience rapidly acquire resistance [3]. We demonstrate that hmUdR and other deoxyuridine analogs synergistically enhance the cytotoxicity of FU in cancer but not normal cells by dramatically increasing the number of single strand breaks
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