Anticancer Properties of Kaempferol on Cellular Signaling Pathways

Abstract

Polyhydroxy compounds are secondary metabolites that are ubiquitous in plants of higher genera. They possess therapeutic properties against a wide spectrum of diseases, including cancers, neurodegenerative disorders, atherosclerosis, as well as cardiovascular disease. The phytochemical flavonol (a type of flavonoid) kaempferol (KMP) (3,5,7-trihydroxy-2-(4-hydroxyphenyl)- 4Hchromen-4-one) is abundant in cruciferous vegetables, including broccoli, kale, spinach, and watercress, as well as in herbs like dill, chives, and tarragon. KMP is predominantly hydrophobic in nature due to its diphenylpropane structure (a characteristic feature of flavonoids). Recent findings have indicated the promise of applying KMP in disease prevention due to its potential antioxidant, antimutagenic, antifungal, and antiviral activities. In the literature, there is evidence that KMP exerts its anticancer effects by modulating critical elements in cellular signal transduction pathways linked to apoptosis, inflammation, angiogenesis, and metastasis in cancer cells without affecting the viability of normal cells. It has been shown that KMP triggers cancer cell death by several mechanisms, including cell cycle arrest, caspase activation, metabolic alteration, and impacting human telomerase reverse-transcriptase gene expression. This review is aimed at providing critical insights into the influence of KMP on the intracellular cascades that regulate metabolism and signaling in breast, ovarian, and cervical cancer cells.

Keywords: Breast cancer; Cancer therapy; Cervical cancer; Chemoresistance.; Natural product; Ovarian cancer.

Scheme 1.

Illustration of the various pathways by which kaempferol (KMP) induces an apoptotic response in breast cancer cells. KMP decreased the uptake of glucose and lactic acid in MCF-7 cells [34]. In addition, KMP damaged the ER in MCF-7 cells inhibiting estradiol-mediated cell growth [35]. Moreover, KMP initiated the caspase cascade by the cleavage of PARP [33]. KMP was shown to induce apoptosis through G2/M cell cycle arrest [–38]. Furthermore, KMP was shown to have facilitated dsDNA damage, leading to increased expression of γH2AX [39, 40].

Scheme 2.

An illustration of kaempferol (KMP) inhibiting the PI3K/AKT signaling pathway, leading to downstream apoptotic effects [43]. KMP was shown to have an effect of decreasing mitochondrial potential, releasing cytochrome c, and thus upregulating the caspase cascade [44].

Scheme 3.

An illustration of the alterations in various cell signaling pathways that are responsible for inducing apoptosis of ovarian cancer cells. KMP causes cell cycle arrest at the G₂/M phase through downregulation of the Chk2/p21/Cdc2 pathway [46]. In addition, KMP inhibits the MEK/ERK pathway [47]. Furthermore, KMP dysregulates the JNK/ERK pathway, facilitating KMP/TRAIL-induced apoptosis of OVCAR-3 [48]. Finally, KMP/DPP regulates cell death by inhibiting the AKT signaling pathway [49].