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Cited by 57Flavonoids in Medical ResearchColorectal Cancer Treatments and StudiesBioactive natural compounds

Diosmetin Exerts Synergistic Effects in Combination with 5-Fluorouracil in Colorectal Cancer Cells

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Kamran, Sareh, Sinniah, Ajantha, Chik, Zamri, Alshawsh, Mohammed Abdullah·2022·Biomedicines
DOI 10.3390/biomedicines10030531PMC PMC8945009
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Abstract

5-Fluorouracil (5-FU) is a chemotherapeutic medication commonly used to treat colorectal cancer (CRC); however, the drug-associated adverse effects and toxicity have greatly affected its clinical use. Exploring another therapeutic strategy that lowers the toxicity of 5-FU while having a synergistic effect against CRC is thus a viable option. Diosmetin, a natural flavonoid, has been shown to inhibit the proliferation of many cancer cells, including CRC cells. This study aims to investigate the synergistic effect of diosmetin and 5-FU on HCT116 and HT29 colorectal cancer cells and to explore the apoptotic activity of this combination. The MTT assay was used to assess the viability of cells treated with monotherapy and combination therapy. The combination index (CI) and dose reduction index (DRI) were calculated using the CompuSyn software (version 1.0). The SynergyFinder 2.0 software was used to calculate the synergy score, while the Combenefit software was employed to perform isobologram analysis and synergism determination. The AO/PI double staining technique was used to detect the apoptotic characteristics of cells, whereas the flow cytometry technique was used to investigate the apoptosis induction and cell cycle arrest in cells. The combination of 5-FU and diosmetin showed a synergistic effect in HCT116 cells with a mean CI value of 0.66 ± 0.4, and an additive effect in HT29 cells with a CI value of 1.0 ± 0.2. The DRI of 5-FU in HCT116 cells was three times lower in the combination therapy compared to monotherapy of 5-FU. AO/PI microscopic examination and Annexin V analysis revealed that the combination-treated cells had more apoptotic cells than the monotherapy-treated cells, which was activated mainly through intrinsic apoptosis pathway. HCT116 cell death was confirmed by mitotic arrest in the G2/M phase. Our findings suggest that 5-FU/diosmetin combination exhibits synergistic effect against HCT116 cancer cells, and potentially reduces the unfavorable adverse effect of 5-FU while enhancing the anticancer efficacy by inducing apoptosis and interrupting mitosis. Further research studies are needed to validate the combination’s anti-tumorigenic activities in a xenograft animal model.

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  • Other studies demonstrating synergistic effects with 5-fluorouracil and compounds such as diosmetin and kaempferol used substantially higher 5-fluorouracil concentrations than this study.

    “This is substantially lower than what has been used in other studies in which synergistic effects have been demonstrated when using 5‐fluorouracil with other compounds, such as diosmetin and kaempferol [34, 35].”

    From Synergistic Potential of Argentatins A and B to Improve 5‐Fluorouracil Cytotoxicity in Colorectal Cancer Cell Models (2024) · cites this paper as [35]

    The Results (§3.2) report synergy between 5-fluorouracil and diosmetin in HCT116 cells at 5-fluorouracil doses of 0.15–1.25 µg/mL. This copy does not establish whether those doses were substantially higher than the citing study’s; the kaempferol study is a separate citation. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Kamran, S., Sinniah, A., Chik, Z., & Alshawsh, M. A.
Affiliations
University of Malaya (MY)
Corresponding author
Alshawsh, Mohammed Abdullah
ORCID
Venue
Biomedicines
Publisher
MDPI AG
Published
2022-02-24
Volume
10
Issue
3
Pages
531
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines10030531
PMC
PMC8945009
OpenAlex
W4213441241
Cited by
57
References
3
Citations by year
2026: 7 · 2025: 17 · 2024: 16 · 2023: 11 · 2022: 4 · 2013: 1
FWCI
7.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
The Malaysian Ministry of Higher Education (((FP103-2019A) Ref: FRGS/1/2019/SKK10/UM/02/3).)
Topics
  • Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioactive natural compounds
Keywords
diosmetin, 5-fluorouracil, colorectal cancer, drug synergy, combination therapy, flavonoids, apoptosis, G2/M cell cycle arrest, HCT116 cells, HT-29 cells, chemotherapy toxicity reduction, mitochondrial apoptosis

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