Kaempferol and its derivatives: Biological activities and therapeutic potential

Abstract

Kaempferol, a natural plant-origin flavonoid, exhibits therapeutic anti-inflammatory, antioxidant, anticancer, antidiabetic, and neuroprotective properties. Kaempferol acts within several distinct mechanisms like apoptotic induction in cancer cells, enzymatic inhibition, signalling pathway inhibition, and downregulation in cell viability during the G₂/M phase of cell division. This review summarizes the therapeutic effects of kaempferol against several health ailments. The recent progress on kaempferol obtained from fruits and vegetables as an antioxidant, anti-inflammatory, anticancer, antidiabetic, and neuroprotective agent and its mechanisms of action are also discussed. In addition, kaempferol has been reported to be present in wastes and byproducts from post-fruit and vegetable processing. Thus, a paradigm shift towards valorizing fruits and vegetable industrial wastes/byproducts to obtain bioactive kaempferol can support the circular economy pillar for generating wealth from waste and for finding a sustainable alternative source.

Keywords

Kaempferol / Therapeutic effects / Bioactivities / Fruits and vegetable wastes / Sustainable alternative sources

Conflict of interest statement

The authors declare that they have no conflict of interest.

Funding

The authors received no extramural funding for the study.

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

SP collected the literature and prepared the manuscript. IUHB designed the original idea, collected the literature and prepared the manuscript. RB reviewed and edited the manuscript. All the authors approved the final version of the manuscript.

References

[1] Li Q, Wei L, Lin S, Chen Y, Lin J, Peng J. Synergistic effect of kaempferol and 5-fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway. Mol Med Rep 2019; 20(1): 728-734.

[2] Rahaman ST, Mondal S. Flavonoids: A vital resource in healthcare and medicine. Pharm Pharmacol Int J 2020; 8(2): 91-104.

[3] Calderon-Montano JM, Burgos-Moron E, Perez-Guerrero C, Lopez-Lazaro M. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem 2011; 11(4): 298-344.

[4] Silva dos Santos J, Gonçalves Cirino JP, de Oliveira Carvalho P, Ortega MM. The pharmacological action of kaempferol in central nervous system diseases: A review. Front Pharmacol 2021; 11. doi: 10.3389/fphar.2020.565700.

[5] Ashrafizadeh M, Tavakol S, Ahmadi Z, Roomiani S, Mohammadinejad R, Samarghandian S. Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress. Phyther Res 2020; 34(5): 911-923.

[6] Häkkinen SH, Kärenlampi SO, Heinonen IM, Mykkänen HM, Törrönen AR. Content of the flavonols quercetin, myricetin, and kaempferol in 25 edible berries. J Agric Food Chem 1999; 47(6): 2274-2279.

[7] Fieschi M, Codignola A, Mosca AML. Mutagenic flavonol aglycones in infusions and in fresh and pickled vegetables. J Food Sci 1989; 54(6): 1492-1495.

[8] Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 2001; 49(6): 3106-3112.

[9] Hertog MGL, Hollman PCH, Hertog MGL, Katan MB. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands. J Agric Food Chem 1992; 40(12): 2379-2383.

[10] Herrmann K. Flavonols and flavones in food plants: A review. Int J Food Sci Technol 1976; 11(5): 433-448.

[11] Folkerts G, Kloek J, Muijsers RBR, Nijkamp FP. Reactive nitrogen and oxygen species in airway inflammation. Eur J Pharmacol 2001; 429(1-3): 251-262.

[12] Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454(7203): 428-435.

[13] Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clin Endocrinol (Oxf) 1997; 47(1): 9-14.

[14] Nardini M, Natella F, Scaccini C. Role of dietary polyphenols in platelet aggregation. A review of the supplementation studies. Platelets 2007; 18(3): 224-243.

[15] Rathee P, Chaudhary H, Rathee S, Rathee D, Kumar V, Kohli K. Mechanism of action of flavonoids as anti-inflammatory agents: A review. Inflamm Allergy Drug Targets 2009; 8(3): 229-235.

[16] Alam W, Khan H, Shah MA, Cauli O, Saso L. Kaempferol as a dietary anti-inflammatory agent: Current therapeutic standing. Molecules 2020; 25(18): 4073.

[17] Wang J, Fang X, Ge L, Cao F, Zhao L, Wang Z, et al. Antitumor, antioxidant and anti-inflammatory activities of kaempferol and its corresponding glycosides and the enzymatic preparation of kaempferol. PLoS One 2018; 13(5): e0197563.

[18] Zhuang Z, Ye G, Huang B. Kaempferol alleviates the interleukin-1β-induced inflammation in rat osteoarthritis chondrocytes via suppression of NF-κB. Med Sci Monit 2017; 23: 3925-3931.

[19] Zhang T, Qiu F, Chen L, Liu R, Chang M, Wang X. Identification and in vitro anti-inflammatory activity of different forms of phenolic compounds in Camellia oleifera oil. Food Chem 2021; 344: 128660.

[20] Hu WH, Dai DK, Zheng BZY, Duan R, Chan GKL, Dong TXX, et al. The binding of kaempferol-3-O-rutinoside to vascular endothelial growth factor potentiates anti-inflammatory efficiencies in lipopolysaccharide-treated mouse macrophage RAW264.7 cells. Phytomedicine 2021; 80: 153400.

[21] Sun Z, Li Q, Hou R, Sun H, Tang Q, Wang H, et al. Kaempferol-3-O-glucorhamnoside inhibits inflammatory responses via MAPK and NF-κB pathways in vitro and in vivo. Toxicol Appl Pharmacol 2019; 364: 22-28.

[22] Khajuria V, Gupta S, Sharma N, Tiwari H, Bhardwaj S, Dutt P, et al. Kaempferol-3-o-β-D-glucuronate exhibit potential anti-inflammatory effect in LPS stimulated RAW 264.7 cells and mice model. Int Immunopharmacol 2018; 57: 62-71.

[23] Guo P, Feng YY. Anti-inflammatory effects of kaempferol, myricetin, fisetin and ibuprofen in neonatal rats. Trop J Pharm Res 2017; 16(8): 1819-1826.

[24] Zhang R, Ai X, Duan Y, Xue M, He W, Wang C, et al. Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways. Biomed Pharmacother 2017; 89: 660-672.

[25] Tang XL, Liu JX, Dong W, Li P, Li L, Hou JC, et al. Protective effect of kaempferol on LPS plus ATP-induced inflammatory response in cardiac fibroblasts. Inflammation 2015; 38(1): 94-101.

[26] Nam SY, Jeong HJ, Kim HM. Kaempferol impedes IL-32-induced monocyte-macrophage differentiation. Chem Biol Interact 2017; 274: 107-115.

[27] Seo EH, Kang J, Kim KH, Cho MC, Lee S, Kim HJ, et al. Detection of expressed IL-32 in human stomach cancer using ELISA and immunostaining. J Microbiol Biotechnol 2008; 18(9): 1606-1612.

[28] Rong Y, Xiang XD, Li YM, Peng ZY, Li JX. IL-32 was involved in cigarette smoke-induced pulmonary inflammation in COPD. Clin Respir J 2015; 9(4): 430-435.

[29] Montoya D, Inkeles MS, Liu PT, Realegeno S, Teles RMB, Vaidya P, et al. IL-32 is a molecular marker of a host defense network in human tuberculosis. Sci Transl Med 2014; 6(250). doi: 10.1126/scitranslmed.3009546.

[30] Devi KP, Malar DS, Nabavi SF, Sureda A, Xiao J, Nabavi SM, et al. Kaempferol and inflammation: From chemistry to medicine. Pharmacol Res 2015; 99: 1-10.

[31] Xie JH, Dong CJ, Nie SP, Li F, Wang ZJ, Shen MY, et al. Extraction, chemical composition and antioxidant activity of flavonoids from Cyclocarya paliurus (Batal.) Iljinskaja leaves. Food Chem 2015; 186: 97-105.

[32] Ibrahim RR, Ibrahim HA, Shabana SS, El-Hosari DG, Ali SA, Mahgoub S, et al. New phenolic compounds from Calothamnus quadrifidus R.Br. aerial parts and their antioxidant activity. Nat Prod Res 2021; 35(23): 5183-5191.

[33] Ghareeb MA, Saad AM, Abdou AM, Refahy LAG, Ahmed WS. A new kaempferol glycoside with antioxidant activity from Chenopodium ambrosioides growing in Egypt. Orient J Chem 2016; 32(6): 3053-3061.

[34] Simunkova M, Barbierikova Z, Jomova K, Hudecova L, Lauro P, Alwasel SH, et al. Antioxidant vs. prooxidant properties of the flavonoid, kaempferol, in the presence of cu(ii) ions: A ROS-scavenging activity, fenton reaction and dna damage study. Int J Mol Sci 2021; 22(4): 1619.

[35] Zang Y, Zhang D, Yu C, Jin C, Igarashi K. Antioxidant and hepatoprotective activity of kaempferol 3-O-β-d-(2,6-di-O-α-l-rhamnopyranosyl)galactopyronoside against carbon tetrachloride-induced liver injury in mice. Food Sci Biotechnol 2017; 26(4): 1071-1076.

[36] Munhoz ACM, Frode TS. Isolated compounds from natural products with potential antidiabetic activity - a systematic review. Curr Diabetes Rev 2018; 14(1): 36-106.

[37] Al-Numair KS, Veeramani C, Alsaif MA, Chandramohan G. Influence of kaempferol, a flavonoid compound, on membrane-bound ATPases in streptozotocin-induced diabetic rats. Pharm Biol 2015; 53(9): 1372-1378.

[38] Ibitoye OB, Uwazie JN, Ajiboye TO. Bioactivity-guided isolation of kaempferol as the antidiabetic principle from Cucumis sativus L. fruits. J Food Biochem 2018; 42(4): e12479.

[39] Sharma D, Kumar Tekade R, Kalia K. Kaempferol in ameliorating diabetes-induced fibrosis and renal damage: An in vitro and in vivo study in diabetic nephropathy mice model. Phytomedicine 2020; 76: 153235.

[40] Alkhalidy H, Moore W, Wang A, Luo J, McMillan RP, Wang Y, et al. Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice. J Nutr Biochem 2018; 58: 90-101.

[41] Alkhalidy H, Moore W, Wang Y, Luo J, McMillan RP, Zhen W, et al. The flavonoid kaempferol ameliorates streptozotocin-induced diabetes by suppressing hepatic glucose production. Molecules 2018; 23(9): 2338.

[42] Zang Y, Zhang L, Igarashi K, Yu C. The anti-obesity and anti-diabetic effects of kaempferol glycosides from unripe soybean leaves in high-fat-diet mice. Food Funct 2015; 6(3): 834-841.

[43] Hussein RM, Mohamed WR, Omar HA. A neuroprotective role of kaempferol against chlorpyrifos-induced oxidative stress and memory deficits in rats via GSK3β-Nrf2 signaling pathway. Pestic Biochem Physiol 2018; 152: 29-37.

[44] Han X, Zhao S, Song H, Xu T, Fang Q, Hu G, et al. Kaempferol alleviates LD-mitochondrial damage by promoting autophagy: Implications in Parkinson’s disease. Redox Biol 2021; 41. doi: 10.1016/j.redox.2021.101911.

[45] Das D, Biswal S, Barhwal KK, Chaurasia OP, Hota SK. Kaempferol inhibits extra-synaptic NMDAR-mediated downregulation of TRkβ in rat hippocampus during hypoxia. Neuroscience 2018; 392: 77-91.

[46] Beg T, Jyoti S, Naz F, Rahul, Ali F, Ali SK, et al. Protective effect of kaempferol on the transgenic drosophila model of Alzheimer’s disease. CNS Neurol Disord Drug Targets 2018; 17(6): 421-429.

[47] Han X, Sun S, Sun Y, Song Q, Zhu J, Song N, et al. Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: Implications for Parkinson disease. Autophagy 2019; 15(11): 1860-1881.

[48] Li WH, Cheng X, Yang YL, Liu M, Zhang SS, Wang YH, et al. Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats. Brain Res 2019; 1722. doi: 10.1016/j.brainres.2019.146361.

[49] Gao W, Wang W, Peng Y, Deng Z. Antidepressive effects of kaempferol mediated by reduction of oxidative stress, proinflammatory cytokines and up-regulation of AKT/β-catenin cascade. Metab Brain Dis 2019; 34(2): 485-494.

[50] de la Garza AL, Garza-Cuellar MA, Silva-Hernandez IA, Cardenas-Perez RE, Reyes-Castro LA, Zambrano E, et al. Maternal flavonoids intake reverts depression-like behaviour in rat female offspring. Nutrients 2019; 11(3): 572.

[51] Cheng X, Yang YL, Yang H, Wang YH, Du GH. Kaempferol alleviates LPS-induced neuroinflammation and BBB dysfunction in mice via inhibiting HMGB1 release and down-regulating TLR4/MyD88 pathway. Int Immunopharmacol 2018; 56: 29-35.

[52] Wu B, Luo H, Zhou X, Cheng CY, Lin L, Liu BL, et al. Succinate-induced neuronal mitochondrial fission and hexokinase Ⅱ malfunction in ischemic stroke: Therapeutical effects of kaempferol. Biochim Biophys Acta Mol Basis Dis 2017; 1863(9): 2307-2318.

[53] Pan X, Liu X, Zhao H, Wu B, Liu G. Antioxidant, anti-inflammatory and neuroprotective effect of kaempferol on rotenone-induced Parkinson’s disease model of rats and SH-S5Y5 cells by preventing loss of tyrosine hydroxylase. J Funct Foods 2020; 74: 104140.

[54] Wang J, Mao J, Wang R, Li S, Wu B, Yuan Y. Kaempferol protects against cerebral ischemia reperfusion injury through intervening oxidative and inflammatory stress induced apoptosis. Front Pharmacol 2020; 11. doi: 10.3389/fphar.2020.00424.

[55] Kubina R, Iriti M, Kabała-Dzik A. Anticancer potential of selected flavonols: Fisetin, kaempferol, and quercetin on head and neck cancers. Nutrients 2021; 13(3). doi: 10.3390/nu13030845.

[56] Imran M, Rauf A, Shah ZA, Saeed F, Imran A, Arshad MU, et al. Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review. Phyther Res 2019; 33(2): 263-275.

[57] Imran M, Salehi B, Sharifi-Rad J, Gondal TA, Saeed F, Imran A, et al. Kaempferol: A key emphasis to its anticancer potential. Molecules 2019; 24(12): 2277.

[58] Marfe G, Tafani M, Indelicato M, Sinibaldi-Salimei P, Reali V, Pucci B, et al. Kaempferol induces apoptosis in two different cell lines via Akt inactivation, bax and SIRT3 activation, and mitochondrial dysfunction. J Cell Biochem 2009; 106(4): 643-650.

[59] Melek FR, Zalabani SME, Ghaly NS, Sabry OM, Fayad W, Boulis AG. Phytoconstituents with cytotoxic activity from Ulmus pumila L. J Appl Pharm Sci 2021; 11(5): 127-134.

[60] Wang F, Wang L, Qu C, Chen L, Geng Y, Cheng C, et al. Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling. BMC Cancer 2021; 21(1): 396.

[61] Yao S, Wang X, Li C, Zhao T, Jin H, Fang W. Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway. Tumor Biol 2016; 37(8): 10247-10256.

[62] Pham HNT, Sakoff JA, Vuong Q Van, Bowyer MC, Scarlett CJ. Screening phytochemical content, antioxidant, antimicrobial and cytotoxic activities of Catharanthus roseus (L.) G. Don stem extract and its fractions. Biocatal Agric Biotechnol 2018; 16: 405-411.

[63] Kim TW, Lee SY, Kim M, Cheon C, Ko SG. Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells. Cell Death Dis 2018; 9(9): 875.

[64] Yang S, Si L, Jia Y, Jian W, Yu Q, Wang M, et al. Kaempferol exerts anti-proliferative effects on human ovarian cancer cells by inducing apoptosis, G₀/G₁ cell cycle arrest and modulation of MEK/ERK and STAT3 pathways . J Buon 2019; 24(3): 975-981.

[65] Wu P, Meng X, Zheng H, Zeng Q, Chen T, Wang W, et al. Kaempferol attenuates ROS-induced hemolysis and the molecular mechanism of its induction of apoptosis on bladder cancer. Molecules 2018; 23(10): 2592.

[66] Chen HJ, Lin CM, Lee CY, Shih NC, Peng SF, Tsuzuki M, et al. Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells. Oncol Rep 2013; 30(2): 925-932.

[67] Moradzadeh M, Tabarraei A, Sadeghnia HR, Ghorbani A, Mohamadkhani A, Erfanian S, et al. Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes. J Cell Biochem 2018; 119(2): 2288-2297.

[68] Sezer ED, Oktay LM, Karadadaş E, Memmedov H, Selvi Gunel N, Sözmen E. Assessing anticancer potential of blueberry flavonoids, quercetin, kaempferol, and gentisic acid, through oxidative stress and apoptosis parameters on HCT-116 cells. J Med Food 2019; 22(11): 111-1126.

[69] Mahgoub S, Hashad N, Ali S, Ibrahim R, Said AM, Moharram FA, et al. Polyphenolic profile of Callistemon viminalis aerial parts: Antioxidant, anticancer and in silico 5-lox inhibitory evaluations. Molecules 2021; 26(9): 2481.

[70] Yathzamiry VGD, Cecilia EGS, Antonio MCJ, Daniel NFS, Carolina FGA, Alberto AVJ, et al. Isolation of polyphenols from soursop (Annona muricata L.) leaves using green chemistry techniques and their anticancer effect. Brazilian Arch Biol Technol 2021; 64: 1-15.

[71] Cai S, Kong Y, Xiao D, Chen Y, Wang Q. Primary aminomethyl derivatives of kaempferol: Hydrogen bond-assisted synthesis, anticancer activity and spectral properties. Org Biomol Chem 2018; 16(11): 1921-1931.

[72] Hung TW, Chen PN, Wu HC, Wu SW, Tsai PY, Hsieh YS, et al. Kaempferol inhibits the invasion and migration of renal cancer cells through the downregulation of AKT and FAK pathways. Int J Med Sci 2017; 14(10): 984-993.

[73] Li Q, Gao B, Siqin B, He Q, Zhang R, Meng X, et al. Gut microbiota: A novel regulator of cardiovascular disease and key factor in the therapeutic effects of flavonoids. Front Pharmacol 2021; 12. doi: 10.3389/fphar.2021.651926.

[74] Yin P, Yang L, Xue Q, Yu M, Yao F, Sun L, et al. Identification and inhibitory activities of ellagic acid- and kaempferol-derivatives from Mongolian oak cups against α-glucosidase, α-amylase and protein glycation linked to type Ⅱ diabetes and its complications and their influence on HepG2 cells’ viability. Arab J Chem 2018; 11(8): 1247-1259.

[75] Kluska M, Juszczak M, Żuchowski J, Stochmal A, Woźniak K. Kaempferol and its glycoside derivatives as modulators of etoposide activity in HL-60 cells. Int J Mol Sci 2021; 22(7): 3520.

[76] Kluska M, Juszczak M, Wysokiński D, Żuchowski J, Stochmal A, Woźniak K. Kaempferol derivatives isolated from Lens culinaris Medik. reduce DNA damage induced by etoposide in peripheral blood mononuclear cells. Toxicol Res (Camb) 2019; 8(6): 896-907.

[77] Olazarán-Santibañez F, Rivera G, Vanoye-Eligio V, Mora-Olivo A, Aguirre-Guzmán G, Ramírez-Cabrera M, et al. Antioxidant and antiproliferative activity of the ethanolic extract of Equisetum myriochaetum and molecular docking of its main metabolites (apigenin, kaempferol, and quercetin) on β-tubulin. Molecules 2021; 26(2): 443.

[78] Pal CBT, Jadeja GC. Deep eutectic solvent-based extraction of polyphenolic antioxidants from onion (Allium cepa L.) peel. J Sci Food Agric 2019; 99(4): 1969-1979.

[79] Di Donato P, Taurisano V, Tommonaro G, Pasquale V, Jiménez JMS, de Pascual-Teresa S, et al. Biological properties of polyphenols extracts from agro industry’s wastes. Waste Biomass Valorizat 2018; 9(9): 1567-1578.

[80] Fermoso FG, Serrano A, Alonso-Fariñas B, Fernández-Bolaños J, Borja R, Rodríguez-Gutiérrez G. Valuable compound extraction, anaerobic digestion, and composting: A leading biorefinery approach for agricultural wastes. J Agric Food Chem 2018; 66(32): 8451-8468.

[81] Teixeira A, Baenas N, Dominguez-Perles R, Barros A, Rosa E, Moreno DA, et al. Natural bioactive compounds from winery by-products as health promoters: A review. Int J Mol Sci 2014; 15(9): 15638-15678.