Abstract
Objective: The majority of chemotherapeutic agents stimulate NF-κB signaling that mediates cell survival, proliferation and metastasis. The natural turmeric non-curcuminoid derivate Calebin A has been shown to suppress cell growth, invasion and colony formation in colorectal cancer cells (CRC) by suppression of NF-κB signaling. Therefore, we hypothesized here that Calebin A might chemosensitize the TNF-β-treated tumor cells and potentiates the effect of 5-Fluorouracil (5-FU) in advanced CRC. Materials and Methods: CRC cells (HCT116) and their clonogenic 5-FU chemoresistant counterparts (HCT116R) were cultured in monolayer or alginate-based 3D tumor environment culture and were treated with/without Calebin A, TNF-β, 5-FU, BMS-345541 and DTT (dithiothreitol). Results: The results showed that TNF-β increased proliferation, invasion and resistance to apoptosis in chemoresistant CRC cells. Pretreatment with Calebin A significantly chemosensitized HCT116R to 5-FU and inhibited the TNF-β-induced enhanced efforts for survival, invasion and anti-apoptotic effects. We found further that Calebin A significantly suppressed TNF-β-induced phosphorylation and nuclear translocation of p65-NF-κB, similar to BMS-345541 (specific IKK inhibitor) and NF-κB-induced tumor-promoting biomarkers (NF-κB, β1-Integrin, MMP-9, CXCR4, Ki67). This was associated with increased apoptosis in HCT116 and HCT116R cells. Furthermore, blocking of p65-NF-κB stimulation by Calebin A was imparted through the downmodulation of p65-NF-κB binding to the DNA and this suppression was turned by DTT. Conclusion: Our findings indicate, for the first time, that Calebin A chemosensitizes human CRC cells to chemotherapy by targeting of the p65-NF-κB signaling pathway.
Highlights
Human colorectal cancer (CRC) is the third most frequent tumor worldwide, one of the most commonly diagnosed cancers and the main reason for tumor-related morbidity and mortality [1].Chemotherapy coupled with surgery is the major treatment option for metastatic CRC
The goal of this paper was to investigate whether Calebin A might have a role in the induction of the chemosensitization effects on wild-type and 5-FU chemoresistant cancer cells to chemotherapeutic agents, by targeting proteins involved in cell survival, proliferation, metastasis and apoptosis in a Tumor Necrosis Factor (TNF)-β-mediated inflammatory environment
Calebin A Downmodulates TNF-β- or 5-FU-Induced Nuclear Translocation of p65-NF-κB in CRC Cells To determine signal transduction pathways participating in the anti-inflammatory actions of Calebin A, we examined transcription factor NF-κB linked with malignity and survival of CRC cells (HCT116, HCT116R) and performed immunofluorescence labeling for p65-NF-κB as described in the Materials and Methods section
Summary
Human colorectal cancer (CRC) is the third most frequent tumor worldwide, one of the most commonly diagnosed cancers and the main reason for tumor-related morbidity and mortality [1]. The main reason for this is an adaptation of the cancer cells to conventional chemotherapy drugs, resulting in relapses, metastasis and death For this reason, there is a huge necessity to develop pharmacologically-safe and relatively inexpensive anti-tumor agents as potential adjunctive treatments to enhance the overall treatment response of patients with CRC [6,7]. Through autocrine and paracrine signaling in the tumor and the tumor environment, NF-κB may be activated by a variety of stimuli including inflammatory cytokines and growth factors promoting cancer cell survival, proliferation, invasion and metastasis [11,12]. Cytokine-induced NF-κB activation is well known to promote chemoresistance of cancer cells to 5-Fluorouracil (5-FU), the potential chemosensitization effect of Calebin A on CRC cells has not been investigated. In the present investigation, we hypothesized that Calebin A could modulate and sensitize 5-FU resistant and non-resistant CRC cells in the TNF-β-promoted inflammatory tumor environment in monolayers and 3D-alginate culture model
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
