Researchers from Rajiv Gandhi Centre for Biotechnology, Kerala have identified Curcumin as a potent chemo-sensitizer to 5‑fluorouracil (5‑FU), an anti-cancer drug. This suggests that curcumin’s use in combination with 5‑FU may lead to significant improvements in the therapeutic index of the drug and in breast cancer treatment outcomes.
Breast cancer is the second most common form of cancer and one of the leading causes of cancer deaths. This disease shows great variability in the drug regimen, prognosis and treatment outcomes, depending on the type of mutation involved in the disease. Mutations generally occur in the BRCA gene, or the estrogen receptor gene, progesterone receptor gene, or as a deficiency in Her2 expression. A rare form of the disease involves mutations in all three genes (triple-negative disease) and generally does not respond to conventional hormonal therapies, or Her2-targeted therapies. These approaches fail because they cannot target ER/PR/Her2/Neu receptors, demanding the need for more research and novel treatment strategies.
Of the many drugs currently available in the market, 5‑fluorouracil (5‑FU) is an anti-metabolite that is used to treat many different forms of cancer, including breast cancer. This compound inhibits the activity of a key enzyme, Thymidylate synthase (TS) in cancer cells. This slows down growth of cancer cells and causes cell death by apoptosis. A wide range of in vivo and in vitro studies have shown that over-expression of the TS enzyme is strongly associated with chemo-resistance to the drug, 5‑FU.
This study shows that using 5‑FU and Curcumin in combination has a synergistic effect, by enhancing cytotoxicity and cell death in breast cancer cell lines. There was no such toxic effect on a normal, immortalized cancer cell line, MCF10A. The combination of 5‑FU and Curcumin showed an increase in the number of cells dying by apoptosis. This effect was achieved by significantly enhancing the cleavage of cell death proteins, procaspase‑8 and procaspase‑9, to their active fragments. Another hallmark of apoptotic cell death, DNA fragmentation viz. a hallmark of apoptosis was also observed with the drug-Curcumin combination used on cancer cells.
In the next step, the authors attempted to identify the signaling pathways in cancer cells that were associated with this synergistic effect. 5‑FU showed a dose-dependent activation of the transcription factor, NF-κB. But curcumin down-regulate activation of NF-κB. Activation of NF-κB induced by 5‑FU is down-regulated by curcumin. Other key pathways, such as AKT and MAPK also upregulated by 5‑FU, and downregulated by curcumin were not involved in synergism.
In order to pinpoint crosstalk between the drug target, Thymidylate synthase and the signaling pathway molecules, the transcription factor, NF-κB was inhibited using SN50, and by IκB double-mutant (DM) transfection. Interestingly, inhibition of NF-κB did not prevent inhibition of TS by 5‑FU, suggesting that it worked downstream of the TS signaling pathway. Curcumin was also capable of sensitizing breast cancer cell lines that differed in their receptor status, highlighting its potential as a chemo-sensitizer.
This specific study has provided new insights into current chemotherapeutic regimen used in breast cancer treatment. While more in vivo studies are necessary to improve our understanding of breast cancer chemotherapy, it appears that Curcumin, with its cost-effectiveness and insignificant toxicity effects, could be established as a conventional chemo-sensitizing agent in chemotherapy.