Calebin A Potentiates the Effect of 5-FU and TNF-β (Lymphotoxin α) against Human Colorectal Cancer Cells: Potential Role of NF-κB.

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.

• Authors: Constanze Buhrmann, Ajaikumar B Kunnumakkara, Bastian Popper, Muhammed Majeed, Bharat B Aggarwal, Mehdi Shakibaei
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 7 (Mar 31 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32244288 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Cinnamates
• Lymphotoxin-alpha
• Monoterpenes
• NF-kappa B
• RELA protein, human
• Transcription Factor RelA
• calebin-A
• Fluorouracil

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival
• Cinnamates (metabolism, pharmacology)
• Colonic Neoplasms (metabolism, pathology)
• Colorectal Neoplasms (metabolism, pathology)
• Fluorouracil (metabolism, pharmacology)
• Humans
• Lymphotoxin-alpha (metabolism, pharmacology)
• Monoterpenes (metabolism)
• NF-kappa B (metabolism)
• Phosphorylation
• Signal Transduction (drug effects)
• Transcription Factor RelA (metabolism)