Potential effect of kaempferol against various malignancies: recent advances and perspectives

Figures & data

Figure 1. A kaempferol molecule.

Figure 2. Health benefits of kaempferol.

Figure 3. Anticancer mechanisms associated with kaempferol. Figure shows kaempferol induces apoptosis in tumour cells through a variety of signalling pathways and mitochondrial mechanisms. Kaempferol inhibits the PI3K/AKT/mTOR pathway, inhibition leads to the activation of pro-apoptotic proteins, p53 and caspases (CASP). Kaempferol suppresses ERK pathway, leads to the activation of MAPK. The inhibition of NF-κB pathway activates pro-apoptotic protein CASP8. Mitochondrial targeting causes cytochrome-c release, which activates caspases.

Table 1. Anticancer potential of kaempferol in the light of published studies.

Types of cancers	Dosage/treatment	Mechanism of action	Cell line(s)	References
Breast	20–100 micromol, 48 h	ERK signalling pathway modulation	MCF-7 and MDA- MB-231 cells	Kim et al., 2008
Breast	10 micromol, 24 h	Inhibited AHR transcription	BT549 and MB-231	MacPherson & Matthews, 2010
Breast	10–100 micromol 24 h	MCT1 Inhibitory action	MCF-7	Azevedo et al., 2015
Bone	25–100 micromol, 48 h	Blockage of MAPK and AP-1 signalling pathways	U-2 OS	Huang et al., 2010
Colon	200 mg per kg per daily for 6 weeks	Decreased ROS production, inhibited lipid peroxidation	HCT-116	Hassan et al., 2021
Colon	0.1–1000 micromol, 48 h	Downregulation of NTRK-3	RKO and HCT-116	Budisan et al., 2019
Oesophageal	In vitro: 30–60 micromol. In vivo: 100 mg per kg, 24–72 h	Inhibition of EGFR signalling pathway	KYSE-150 and Eca1-09 cells	Yao et al., 2016
Fibro sarcoma	10–100 micromol, 24 h	Blockage of NF-κB pathway	HT-1080	Choi, Lee, et al., 2015
Head and neck	70–280 micromol, 48 and 72 h	Increased apoptosis reduced migration	Cal27 and HEp2	Catalán et al., 2020
Liver	40 micromol, 24–72 h	Activated mitochondrial signalling pathway and inhibited PI3K/mTOR/MMP signalling pathways	Huh7, HepG2, Huh1 SKHep-1, PLC/PRF/5, Hep3B and HLF	Yang et al., 2021b
Liver	2.5–100 micromol, 24 and 48 h	Enhanced release of cytochrome-C via ROS generation before cytotoxicity followed	Hepatocytes	Seydi et al., 2018
Lung	1–50 micromol, 24–72 h	Downregulated inhibitor of NF-κB pathways	A-549 and NCIH-460	Fouzder et al., 2021
Lung	5–20 micromol, 24–48 h	ERK1/2 signalling pathway modulation	A549	Tu et al., 2016
Brain	50 micromol, 48–96 h	Induced activation IRE1a -XBP1 pathways	IMR-32 and Neuro-2A	Abdullah et al., 2019
Brain	50–200 micromol for 48 h	Increased apoptosis	U-87 and U-251 cells	Siegelin et al., 2008
Ovarian	0–80 micromol Cisplatin with other chemicals of 0–20 micromols, 24 h	Apoptosis caused by downregulation of cMyc	OVCAR-3	Fouzder et al., 2021
Ovarian	40 micromol/ml kaempferol with cisplatin (0, 20 micromol/ml) for 24 h	PI3K/Akt signalling pathway modulation	A2780	Tu et al., 2016
Pancreatic	In vitro: 2.5–1000 μmol per litre. In vivo: 25 to100 mg per kg, 48 h for 7 days	Induction of ROSdependent apoptosis via Akt/mTOR signalling	PANC1, Miapaca2 cells	Wang et al., 2021
Pancreatic	Multiple doses for 72 h	PI3K/AKT signalling pathway modulation	PANC-1 and BxPC-3 cell lines	Zhang et al., 2021
Prostate	5–15 micromol, 24–144 h	Inhibited cell proliferation through androgen-dependent pathways	LNCaP, PC-3	Da et al., 2019
Renal	50–150 micromol, 24–72 h	Inhibited MAPK signalling	786O, 769P	Song et al., 2014

Kim, B.-W., Lee, E.-R., Min, H.-M., Jeong, H.-S., Ahn, J.-Y., Kim, J.-H., Choi, H.-Y., Choi, H., Kim, E. Y., Park, S. P., & Cho, S.-G. (2008). Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition. Cancer Biology & Therapy, 7(7), 1080–1089. 48. https://doi.org/10.4161/cbt.7.7.6164

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MacPherson, L., & Matthews, J. (2010). Inhibition of aryl hydrocarbon receptor dependent transcription by resveratrol or kaempferol is independent of estrogen receptor α expression in human breast cancer cells. Cancer Letters, 299(2), 119–129. https://doi.org/10.1016/j.canlet.2010.08.010

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Azevedo, C., Correia-Branco, A., Araújo, J. R., Guimaraes, J. T., Keating, E., & Martel, F. (2015). The chemopreventive effect of the dietary compound kaempferol on the MCF-7 human breast cancer cell line is dependent on inhibition of glucose cellular uptake. Nutrition and Cancer, 67(3), 504–513. https://doi.org/10.1080/01635581.2015.1002625

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Huang, W. W., Chiu, Y. J., Fan, M. J., Lu, H. F., Yeh, H. F., Li, K. H., Chen, P. Y., Chung, J. G., & Yang, J. S. (2010). Kaempferol induced apoptosis via endoplasmic reticulum stress and mitochondria-dependent pathway in human osteosarcoma U-2 OS cells. Molecular Nutrition & Food Research, 54(11), 1585–1595. https://doi.org/10.1002/mnfr.201000005

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Hassan, E. S., Hassanein, N. M., & Ahmed, H. M. S. (2021). Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis. Journal of Pharmacological Sciences, 145(1), 29–41. https://doi.org/10.1016/j.jphs.2020.10.005

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Yao, S., Wang, X., Li, C., Zhao, T., Jin, H., & Fang, W. (2016). Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway. Tumor Biology, 37(8), 10247–10256. https://doi.org/10.1007/s13277-016-4912-6

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Choi, Y. J., Lee, Y. H., & Lee, S.-T. (2015). Galangin and kaempferol suppress phorbol12-myristate-13-acetate-induced matrix metalloproteinase-9 expression in human fibrosarcoma HT-1080 c. Molecules and Cells, 38(2), 151.

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Catalán, M., Rodríguez, C., Olmedo, I., Carrasco-Rojas, J., Rojas, D., MolinaBerríos, A., Díaz-Dosque, M., & Jara, J. A. (2020). Kaempferol induces cell death and sensitizes human head and neck squamous cell carcinoma cell lines to cisplatin. In W. E. Crusio, H. Dong, H. H. Radeke, N. Rezaei, O. Steinlein, & J. Xiao (Eds.), Cell biology and translational medicine (Vol. 12, pp. 95–109). Springer.

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Seydi, E., Salimi, A., Rasekh, H. R., Mohsenifar, Z., & Pourahmad, J. (2018). Selective cytotoxicity of luteolin and kaempferol on cancerous hepatocytes obtained from rat model of hepatocellular carcinoma: Involvement of ROSmediated mitochondrial targeting. Nutrition and Cancer, 70(4), 594–604. https://doi.org/10.1080/01635581.2018.1460679

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Fouzder, C., Mukhuty, A., & Kundu, R. (2021). Kaempferol inhibits Nrf2 signaling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells. Archives of Biochemistry and Biophysics, 697, 108700. https://doi.org/10.1016/j.abb.2020.108700

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Tu, L. Y., Pi, J., Jin, H., Cai, J. Y., & Deng, S. P. (2016). Synthesis, characterization and anti-cancer activity of kaempferol-zinc(II) complex. Bioorganic & Medicinal Chemistry Letters, 26(11), 2730–2734. https://doi.org/10.1016/j.bmcl.2016.03.091

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Abdullah, A., Talwar, P., d’Hellencourt, C. L., & Ravanan, P. (2019). IRE 1α is critical for kaempferol-induced neuroblastoma differentiation. The FEBS Journal, 286(7), 1375–1392. https://doi.org/10.1111/febs.14776

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Siegelin, M. D., Reuss, D. E., Habel, A., Herold-Mende, C., & Von Deimling, A. (2008). The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin. Molecular Cancer Therapeutics, 7(11), 3566–3574.

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Zhang, Z., Guo, Y., Chen, M., Chen, F., Liu, B., & Shen, C. (2021). Kaempferol potentiates the sensitivity of pancreatic cancer cells to erlotinib via inhibition of the PI3K/AKT signaling pathway and epidermal growth factor receptor. Infammopharmacology, 29(5), 1587–1601. https://doi.org/10.1007/s10787-021-00848-1

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Da, J., Xu, M., Wang, Y., Li, W., Lu, M., & Wang, Z. (2019). Kaempferol promotes apoptosis while inhibiting cell proliferation via androgen-dependent pathway and suppressing vasculogenic mimicry and invasion in prostate cancer. Analytical Cellular Pathology, 2019, 10.

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