White light-mediated Cu (II)–5FU interaction augments the chemotherapeutic potential of 5-FU: an in vitro study

Abstract

5-Fluorouracil (5-FU) is a potent photosensitizer used in colon and rectal cancers. 5-FU on galvanostatic electrolysis or radiation-induced oxidation of aqueous solution yields N(1)-C(5)-linked dimmer hydrate of 5-FU. Copper is presently associated with chromatin; in cancer cells the concentration of copper is very high. It has been shown to be capable of mediating the action of several anticancer drugs through the production of reactive oxygen species (ROS). The objective of the present study is to determine the Cu (II)-mediated anticancer mechanism of 5-FU under photo-illumination as well as 5-FU alone. We have shown that a pro-oxidant action was enhanced when Cu (II) was used with 5-FU as compared to 5-FU alone. This may be due to the inhibition of dimerization of 5-FU when present in combination with Cu (II) under photo-illumination. It was also shown that 5-FU alone as well as in combination with Cu (II) was able to generate oxidative stress in lymphocyte which is inhibited by scavengers of ROS. Moreover, the results of Fourier-transformed infrared spectra lead to the conclusion that the dimerization of 5-FU was inhibited when used in combination with Cu (II). It was due to the interaction of 5-FU with Cu (II). Hence, we propose that during chemoradiotherapy with 5-FU, the endogenous copper is mobilized by 5-FU, leading to the generation of ROS which cause oxidative stress and possibly cancer cell death by apoptosis.

Assessment of sequential combination of 5-fluorouracil-loaded-chitosan-nanoparticles and ALA-photodynamic therapy on HeLa cell line

“…As PDT belongs to treatment modalities that generate ROS overproduction, generation of ROS was also analyzed in the present study. In addition, 5-Fu generates oxidative stress while its action is favored in a pro-oxidant cellular environment as generated by PDT [26,27]. In our study, ROS production was higher in the cells treated with …”

“…incorporation into DNA leading to their break [24,25]. Some studies also have shown that pro-oxidant actions could enhance the antitumor efficacy of 5-Fu [26,27]. Therefore, it is expected that 5-Fu increases its effectiveness when it is combined with therapies that induce oxidative effect as PDT.…”

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

“…Following metabolic transformation to 5-fluoro-2-deoxyuridine monophosphate, it irreversibly inhibits thymidylate synthase resulting in suppression of thymine nucleotide synthesis driving apoptosis in malignant cells and even in normally replicating cells [2]. Thus, 5-FU exhibits significant toxicity and adverse actions that curbs its clinical use including leucopenia, mucositis, cardio-, hepato- and nephrotoxicities.…”

Calcitriol–copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma

“…Since elevation in copper levels can be as high as two to five folds in malignancies [5], this metabolic difference is being actively targeted to develop strategies to combat the disease. It has been previously shown that standard chemotherapeutic drugs, such as cisplatin [6], methotrexate [7], 5-flourouracil [8] and cyclophosphamide [9] and naturally occurring chemotherapeutic compounds, such as plant derived polyphenolic compounds [10,11] also interact with cellular copper, and this interact may in part, be responsible for their chemotherapeutic effects.…”