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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Curcumin Sensitizes Colorectal Cancer Cells to TRAIL-Mediated Apoptosis

  • Erika Rimondi1
  • Marta Manfredini2
  • Francesca Nigro2
  • Arianna Gonelli3
  • Daniela Milani2
  • Claudio Celeghini2
  • Maurizio Previati2
  • Annalisa Marcuzzi2
  1. 1Department of Translational Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
  2. 2Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
  3. 3Department of Environmental Sciences and Prevention, University of Ferrara, 44121 Ferrara, Italy
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Abstract

Colorectal cancer (CRC) remains a major clinical challenge due to resistance to conventional cell death-inducing therapies. TRAIL selectively induces apoptosis in cancer cells via death receptors, but its effectiveness in preclinical models is limited by tumor resistance mechanisms. Curcumin, a natural polyphenol, modulates multiple survival and apoptotic pathways and has been proposed as a sensitizing agent to overcome TRAIL resistance. Here, we investigated the combinatorial effects of TRAIL and curcumin in the HCT116 colorectal cancer cell model. Cells were treated with TRAIL, curcumin, or their combination for 24 and 48 h, evaluating apoptosis, viability, and underlying mechanisms. Curcumin significantly enhanced TRAIL-induced apoptosis (p < 0.0001) and further reduced MTT-derived metabolic activity (p < 0.01) compared with TRAIL treatment alone. This effect remained evident after 48 h, although the stability and persistence of TRAIL activity were not directly assessed. Mechanistically, combined treatment enhanced PARP cleavage, γ-H2AX phosphorylation, and BAX and Caspase-3 cleavage, while downregulating anti-apoptotic IAP family members. Notably, cotreatment also promoted pyroptosis, shown by characteristic morphological changes (p < 0.0001) and increased Gasdermin-E cleavage. These findings indicate that curcumin sensitizes CRC cells to TRAIL by engaging both apoptotic and pyroptotic pathways, suggesting a potential approach to counteract both TRAIL and multidrug resistance in colorectal cancer.

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Cite

BibTeXRIS
BibTeX
@article{rimondi2026curcumin,
  title = {{Curcumin Sensitizes Colorectal Cancer Cells to TRAIL-Mediated Apoptosis}},
  author = {Erika Rimondi and Marta Manfredini and Francesca Nigro and Arianna Gonelli and Daniela Milani and Claudio Celeghini and Maurizio Previati and Annalisa Marcuzzi},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219444},
  url = {https://www.mdpi.com/1422-0067/27/21/9444},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Curcumin Sensitizes Colorectal Cancer Cells to TRAIL-Mediated Apoptosis
AU  - Erika Rimondi
AU  - Marta Manfredini
AU  - Francesca Nigro
AU  - Arianna Gonelli
AU  - Daniela Milani
AU  - Claudio Celeghini
AU  - Maurizio Previati
AU  - Annalisa Marcuzzi
PY  - 2026
DA  - 2026/10/23
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219444
UR  - https://www.mdpi.com/1422-0067/27/21/9444
AB  - Colorectal cancer (CRC) remains a major clinical challenge due to resistance to conventional cell death-inducing therapies. TRAIL selectively induces apoptosis in cancer cells via death receptors, but its effectiveness in preclinical models is limited by tumor resistance mechanisms. Curcumin, a natural polyphenol, modulates multiple survival and apoptotic pathways and has been proposed as a sensitizing agent to overcome TRAIL resistance. Here, we investigated the combinatorial effects of TRAIL and curcumin in the HCT116 colorectal cancer cell model. Cells were treated with TRAIL, curcumin, or their combination for 24 and 48 h, evaluating apoptosis, viability, and underlying mechanisms. Curcumin significantly enhanced TRAIL-induced apoptosis (p < 0.0001) and further reduced MTT-derived metabolic activity (p < 0.01) compared with TRAIL treatment alone. This effect remained evident after 48 h, although the stability and persistence of TRAIL activity were not directly assessed. Mechanistically, combined treatment enhanced PARP cleavage, γ-H2AX phosphorylation, and BAX and Caspase-3 cleavage, while downregulating anti-apoptotic IAP family members. Notably, cotreatment also promoted pyroptosis, shown by characteristic morphological changes (p < 0.0001) and increased Gasdermin-E cleavage. These findings indicate that curcumin sensitizes CRC cells to TRAIL by engaging both apoptotic and pyroptotic pathways, suggesting a potential approach to counteract both TRAIL and multidrug resistance in colorectal cancer.
SN  - 1422-0067
ER  -