Curcumin potentiates antitumor activity of 5-fluorouracil in a 3D alginate tumor microenvironment of colorectal cancerReportar como inadecuado




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BMC Cancer

, 15:250

Experimental therapeutics and drug development

Abstract

BackgroundTo overcome the limitations of animal-based experiments, 3D culture models mimicking the tumor microenvironment in vivo are gaining attention. Herein, we investigated an alginate-based 3D scaffold for screening of 5-fluorouracil 5-FU or-and curcumin on malignancy of colorectal cancer cells CRC.

MethodsThe potentiation effects of curcumin on 5-FU against proliferation and metastasis of HCT116 cell and its corresponding isogenic 5-FU-chemoresistant cells HCT116R were examined in a 3D-alginate tumor model.

ResultsCRC cells encapsulated in alginate were able to proliferate in 3D-colonospheres in a vivo-like phenotype and invaded from alginate. During cultivation of cells in alginate, we could isolate 3 stages of cells, 1 alginate proliferating 2 invasive and 3 adherent cells. Tumor-promoting factors CXCR4, MMP-9, NF-κB were significantly increased in the proliferating and invasive compared to the adherent cells, however HCT116R cells overexpressed factors in comparison to the parental HCT116, suggesting an increase in malignancy behavior. In alginate, curcumin potentiated 5-FU-induced decreased capacity for proliferation, invasion and increased more sensitivity to 5-FU of HCT116R compared to the HCT116 cells. IC50 for HCT116 to 5-FU was 8nM, but co-treatment with 5 μM curcumin significantly reduced 5-FU concentrations in HCT116 and HCT116R cells 0.8nM, 0.1nM, respectively and these effects were accompanied by down-regulation of NF-κB activation and NF-κB-regulated gene products.

ConclusionsOur results demonstrate that the alginate provides an excellent tumor microenvironment and indicate that curcumin potentiates and chemosensitizes HCT116R cells to 5-FU-based chemotherapy that may be useful for the treatment of CRC and to overcome drug resistance.

KeywordsHuman colon cancer Alginate Metastasis Curcumin 5-FU Chemosensitization AbbreviationsATAmbient temperature

CRCColorectal cancer cells

CXCRC-X-C chemokine receptor

DMEMDulbecco’s modified Eagle’s medium

FBSFetal bovine serum

5-FU5-fluorouracil

MCMitochondrial changes

MMPMatrix metalloproteinase

MTT3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide

NF-κBNuclear factor-κB

PBSPhosphate buffered saline

SDS-PAGESodium dodecyl sulfate-polyacrylamide gel electrophoresis

TEMTransmission electron microscope

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Autor: Mehdi Shakibaei - Patricia Kraehe - Bastian Popper - Parviz Shayan - Ajay Goel - Constanze Buhrmann

Fuente: https://link.springer.com/







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