Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5-fluorouracil

Abstract

5-Fluorouracil (5-FU) is the first rationally designed antimetabolite, which achieves its therapeutic efficacy through inhibition of the enzyme thymidylate synthase (TS), which is essential for the synthesis and repair of DNA. However, prolonged exposure to 5-FU induces TS overexpression, which leads to 5-FU resistance in cancer cells. Several studies have identified curcumin as a potent chemosensitizer against chemoresistance induced by various chemotherapeutic drugs. In this study, we report for the first time, with mechanism-based evidences, that curcumin can effectively chemosensitize breast cancer cells to 5-FU, thereby reducing the toxicity and drug resistance. We found that 10 μM 5-FU and 10 μM curcumin induces a synergistic cytotoxic effect in different breast cancer cells, independent of their receptor status, through the enhancement of apoptosis. Curcumin was found to sensitize the breast cancer cells to 5-FU through TS-dependent downregulation of nuclear factor-κB (NF-κB), and this observation was confirmed by silencing TS and inactivating NF-κB, both of which reduced the chemosensitizing efficacy of curcumin. Silencing of TS suppressed 5-FU-induced NF-κB activation, whereas inactivation of NF-κB did not affect 5-FU-induced TS upregulation, confirming that TS is upstream of NF-κB and regulates the activation of NF-κB in 5-FU-induced signaling pathway. Although Akt/PI3kinase and mitogen-activated protein kinase pathways are activated by 5-FU and downregulated by curcumin, they do not have any role in regulating the synergism. As curcumin is a pharmacologically safe and cost-effective compound, its use in combination with 5-FU may improve the therapeutic index of 5-FU, if corroborated by in vivo studies and clinical trials.

Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance—Implications for IGF-II and IGF-IR–Targeted Therapy

“…Activation of the AKT pathway in 5-FU chemoresistant ESCC cells and tumor xenografts has been reported (34,35), and a recent study showed that AKT is upstream of thymidylate synthase in the 5-FU signaling events (36). Therefore, our data showing significant suppression of p-AKT and thymidylate synthase by cixutumumab treatment suggest that inhibiting the PI3K/AKT pathway and thymidylate synthase expression may be the mechanisms by which cixutumumab helps cancer cells overcome 5-FU resistance.…”

Recent advances of curcumin and its analogues in breast cancer prevention and treatment

“…The co-administration of 5-FU and curcumin results in inhibition of DNA synthesis in MDA-MB-231 cells and enhanced LD 50. 120 A synergistic administration of EGCG and curcumin results in inhibition on cell growth and induced apoptosis in MCF-7 cells that are both doxorubicin (DOX) sensitive and resistant. Qian-Mei et al, 121 studied the combination of curcumin and mitomycin C (MMC) on a MCF-7 xenograft mouse model and observed an increase in apoptosis and inhibition of tumour growth via the ERK pathway.…”

Gossypol sensitizes the antitumor activity of 5-FU through down-regulation of thymidylate synthase in human colon carcinoma cells

“…However, studies indicate that 5-FU treatment induces TS expression, which might lead to chemoresistance [26,27]. The low level of TS is generally thought to sensitize cells to 5-FU.…”