Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway

Li, Qiongyu; Wei, Lihui; Lin, Shan; Chen, Youqin; Lin, Jiumao; Peng, Jun

doi:10.3892/mmr.2019.10296

Cited by 80Flavonoids in Medical ResearchPI3K/AKT/mTOR signaling in cancerPhytochemicals and Antioxidant Activities

Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway

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Li, Qiongyu, Wei, Lihui, Lin, Shan, Chen, Youqin, Lin, Jiumao, Peng, Jun·2019·Molecular Medicine Reports

DOI 10.3892/mmr.2019.10296

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Abstract

Combination chemotherapy with chemosensitizers can exert synergistic therapeutic effects, reduce toxicity, and delay the induction of drug resistance. In the present study, the antitumor effects were investigated, and the possible underlying mechanisms of kaempferol combined with 5‑fluorouracil (5‑FU) in colorectal cancer cells were explored. HCT‑8 or HCT‑116 cells were treated with various concentrations of kaempferol and/or 5‑FU for the indicated time‑points. An MTT assay was used to determine cell viability, whereas the synergistic effects were assessed by calculating the combination indices of kaempferol and 5‑FU. Annexin V analysis and Hoechst staining were used to determine cell apoptosis. q‑PCR and western blotting were performed to determine the expression levels of Bax, Bcl‑2, thymidylate synthase (TS), PTEN, PI3K, AKT, and p‑AKT. The combination of kaempferol and 5‑FU was determined to be more effective in inhibiting cell viability than either of the agents alone. The inhibition of tumors in response to kaempferol and 5‑FU was associated with the reduction in proliferation ability and stimulation of apoptosis. The protein results indicated that kaempferol and 5‑FU could significantly upregulate the expression levels of Bax and downregulate the expression levels of Bcl‑2 and TS. Furthermore, the combination treatment greatly inhibited the activation of the PI3K/Akt pathway, suggesting the involvement of this pathway in the synergistic effects. The present study demonstrated that kaempferol has a synergistic effect with 5‑FU by inhibiting cell proliferation and inducing apoptosis in colorectal cancer cells via suppression of TS or attenuation of p‑Akt activation. The combination of kaempferol and 5‑FU may be used as an effective therapeutic strategy for colorectal cancer.

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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 [34]

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Authors: Li, Q., Wei, L., Lin, S., Chen, Y., Lin, J., & Peng, J.
Affiliations: Fujian University of Traditional Chinese Medicine (CN)
Rainbow Babies & Children's Hospital (US)
ORCID: Li, Qiongyu
Wei, Lihui
Lin, Shan
Chen, Youqin
Lin, Jiumao
Peng, Jun
Venue: Molecular Medicine Reports
Publisher: Spandidos Publications
Published: 2019-05-27
Volume: 20
Issue: 1
Pages: 728-734
ISSN: 1791-2997 (ISSN-L)
1791-3004
DOI: 10.3892/mmr.2019.10296
OpenAlex: W2946417430
Cited by: 79
References: 46
Citations by year: 2026: 6 · 2025: 7 · 2024: 11 · 2023: 12 · 2022: 22 · 2021: 12 · 2020: 8 · 2019: 1
FWCI: 6.70
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Molecular Medicine Reports (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
Keywords: kaempferol, 5-fluorouracil, colorectal cancer, combination chemotherapy, synergistic effect, PI3K/Akt signaling, apoptosis, thymidylate synthase, Bax/Bcl-2 ratio, cell proliferation, chemosensitizers, HCT116 cells, HCT-8 cells
MeSH terms: Antineoplastic Agents, Drug Synergism, Fluorouracil, Humans, Colorectal Neoplasms, Signal Transduction, Apoptosis, Phosphatidylinositol 3-Kinases, Kaempferols, HCT116 Cells, Cell Proliferation, Proto-Oncogene Proteins c-akt

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Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway

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