Curcumin abrogates bile-induced NF-κB activity and DNA damage in vitro and suppresses NF-κB activity whilst promoting apoptosis in vivo, suggesting chemopreventative potential in Barrett’s oesophagus

Rawat, Nihit; Al-Hamdani, Ali; McAdam, Elizabeth; Cronin, James G.; Eltahir, Zakaria; Lewis, Paul D.; Griffiths, Paul; Baxter, J. N.; Jenkins, Gareth

doi:10.1007/s12094-012-0799-x

Cited by 30 publications

(18 citation statements)

References 49 publications

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“…Quercetin, silymarin and curcumin are antioxidants that have been reported to protect hepatocytes against cholestatic liver damage434445. Our study showed that these compounds also protected hiHeps against DCA-mediated cholestatic toxicity (Fig.…”

Section: Discussionsupporting

confidence: 53%

Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model

Gao

et al. 2016

Sci Rep

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Drug-induced cholestasis is a leading cause of drug withdrawal. However, the use of primary human hepatocytes (PHHs), the gold standard for predicting cholestasis in vitro, is limited by their high cost and batch-to-batch variability. Mature hepatocyte characteristics have been observed in human induced hepatocytes (hiHeps) derived from human fibroblast transdifferentiation. Here, we evaluated whether hiHeps could biosynthesize and excrete bile acids (BAs) and their potential as PHH alternatives for cholestasis investigations. Quantitative real-time PCR (qRT-PCR) and western blotting indicated that hiHeps highly expressed BA synthases and functional transporters. Liquid chromatography tandem mass spectrometry (LC-MS/MS) showed that hiHeps produced normal intercellular unconjugated BAs but fewer conjugated BAs than human hepatocytes. When incubated with representative cholestatic agents, hiHeps exhibited sensitive drug-induced bile salt export pump (BSEP) dysfunction, and their response to cholestatic agent-mediated cytotoxicity correlated well with that of PHHs (r2 = 0.8032). Deoxycholic acid (DCA)-induced hepatotoxicity in hiHeps was verified by elevated aspartate aminotransferase (AST) and γ-glutamyl-transferase (γ-GT) levels. Mitochondrial damage and cell death suggested DCA-induced toxicity in hiHeps, which were attenuated by hepatoprotective drugs, as in PHHs. For the first time, hiHeps were reported to biosynthesize and excrete BAs, which could facilitate predicting cholestatic hepatotoxicity and screening potential therapeutic drugs against cholestasis.

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Section: Discussionsupporting

confidence: 53%

Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model

Gao

et al. 2016

Sci Rep

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“…In addition, curcumin inhibited NF-κB -induced production of CXCL1 and CXCL2 in breast cancer cells [ 72 ]. Curcumin can abrogate NF-κB pathway in multiple cancer cells [ 73 ], including breast cancer [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ], colorectal cancer [ 82 , 83 ], human oral squamous carcinoma [ 84 ], human bladder cancer [ 85 , 86 ], cutaneous T-cell lymphoma [ 87 , 88 ], pancreatic cancer [ 89 ], head and neck squamous cell carcinoma [ 90 , 91 ], adenoid cystic carcinoma [ 92 ], glioblastoma [ 93 , 94 ], human tongue squamous cell carcinoma [ 95 ], human biliary cancer [ 96 ], medulloblastoma [ 97 ], gastric cancer [ 98 ], lymphoma [ 99 , 100 ], Myeloid-derived suppressor cells [ 101 ], ovarian cancer [ 102 ], T-cell and NFAT activation [ 103 ], rhabdomyosarcoma [ 104 , 105 ], esophageal adenocarcinoma [ 106 , 107 ], esophageal squamous cell carcinoma [ 108 , 109 ], human epidermoid carcinoma [ 110 ], prostate cancer [ 111 , 112 , 113 ], non-Hodgkin’s lymphoma [ 114 ], Hodgkin’s lymphoma [ …”

Section: Molecular Targets Modulated By Curcuminmentioning

confidence: 99%

The Multifaceted Role of Curcumin in Cancer Prevention and Treatment

et al. 2015

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Despite significant advances in treatment modalities over the last decade, neither the incidence of the disease nor the mortality due to cancer has altered in the last thirty years. Available anti-cancer drugs exhibit limited efficacy, associated with severe side effects, and are also expensive. Thus identification of pharmacological agents that do not have these disadvantages is required. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa), is one such agent that has been extensively studied over the last three to four decades for its potential anti-inflammatory and/or anti-cancer effects. Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. These anti-cancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also abrogates proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. The current review focuses on the diverse molecular targets modulated by curcumin that contribute to its efficacy against various human cancers.

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“…NF-κB is a family of direct transcription factors which can bind to specific DNA sequences in target genes involving in immunoregulation, inflammation, growth, carcinogenesis and apoptosis (18,19). Activated NF-κB can function as an oncogene in a variety of tumors to promote tumor cell proliferation and invasion, induce angiogenesis and metastasis, and prevent apoptosis (20,21).…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Lan

Yang

Han

et al. 2015

International Journal of Oncology

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Abstract. The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC 50 ) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC 50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

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Curcumin abrogates bile-induced NF-κB activity and DNA damage in vitro and suppresses NF-κB activity whilst promoting apoptosis in vivo, suggesting chemopreventative potential in Barrett’s oesophagus

Abstract: Curcumin abrogated bile-driven effects in vitro. The in vivo data also suggests that curcumin supplementation had beneficial effects (increased apoptosis, potentially reduced NF-κB activity) in the Barrett's tissues themselves, despite poor delivery of the curcumin to the oesophagus.

Cited by 30 publications

References 49 publications

Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model

Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: A novel in vitro cholestatic model

The Multifaceted Role of Curcumin in Cancer Prevention and Treatment

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

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