Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-B Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

  • Nutrients. 2019 Dec 1;11(12):2904. doi: 10.3390/nu11122904.
Constanze Buhrmann  1 ,  Bastian Popper  2  3 ,  Ajaikumar B Kunnumakkara  4 ,  Bharat B Aggarwal  5 ,  Mehdi Shakibaei  1
Affiliations
  • 1. Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany.
  • 2. Biomedical Center, Core facility animal models, Ludwig-Maximilian-University Munich, D-82152 Martinsried, Germany.
  • 3. Institute of Pathology, School of Medicine, Technical University of Munich, D-81675 Munich, Germany.
  • 4. Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
  • 5. Inflammation Research Center, San Diego, CA 92126, USA.
PMID: 31805741 DOI: 10.3390/nu11122904
Abstract

Objective: Natural polyphenol Calebin A has been recently discovered as a novel derivate from turmeric with anti-cancer potential. Pro-inflammatory cytokine TNF-β (lymphotoxin α) is a stimulant for Cancer cell malignity via activation of NF-B pathway, also in colorectal Cancer (CRC). Here, we investigated the potential of Calebin A to suppress TNF-β-induced NF-B signalling in CRC.

Materials and methods: Three distinct CRC cell lines (HCT116, RKO, SW480) were treated in monolayer or 3-dimensional alginate culture with TNF-β, Calebin A, curcumin, BMS-345541, dithiothreitol (DTT) or antisense oligonucleotides-(ASO) against NF-B.

Results: Calebin A suppressed dose-dependent TNF-β-induced CRC cell vitality and proliferation in monolayer culture. Further, in alginate culture, Calebin A significantly suppressed TNF-β-enhanced colonosphere development, as well as invasion and colony formation of all three CRC cell lines investigated. Calebin A specifically blocked TNF-β-induced activation and nuclear translocation of p65-NF-B, similar to curcumin (natural NF-B inhibitor), BMS-345541 (specific IKK Inhibitor) and ASO-NF-B. Moreover, Immunofluorescence and Immunoblotting showed that Calebin A, similar to curcumin or BMS-345541 suppressed TNF-β-induced activation and nuclear translocation of p65-NF-B and the transcription of NF-B-promoted biomarkers associated with proliferation, migration and Apoptosis, in a dose- and time-dependent manner. Those findings were potentiated by the specific treatment of extracted nuclei with DTT, which abrogated Calebin A-mediated nuclear p65-NF-B-inhibition and restored p65-NF-B-activity in the nucleus.

Conclusion: Overall, these results demonstrate, for the first time, that multitargeted Calebin A has an anti-cancer capability on TNF-β-induced malignities through inhibitory targeting of NF-B activation in the cytoplasm, as well as by suppressing the binding of p65-NF-B to DNA.

Keywords
Calebin A; Colorectal Cancer; Curcumin; Metastasis; TNF-β (Lymphotoxin), NF-B.
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