Kaempferol: A Key Emphasis to Its Anticancer Potential

A marked decrease in human cancers, including breast cancer, bone cancer, and cervical cancer, has been linked to the consumption of vegetable and fruit, and the corresponding chemoprotective effect has been associated with the presence of several active molecules, such as kaempferol. Kaempferol is a major flavonoid aglycone found in many natural products, such as beans, bee pollen, broccoli, cabbage, capers, cauliflower, chia seeds, chives, cumin, moringa leaves, endive, fennel, and garlic. Kaempferol displays several pharmacological properties, among them antimicrobial, anti-inflammatory, antioxidant, antitumor, cardioprotective, neuroprotective, and antidiabetic activities, and is being applied in cancer chemotherapy. Specifically, kaempferol-rich food has been linked to a decrease in the risk of developing some types of cancers, including skin, liver, and colon. The mechanisms of action include apoptosis, cell cycle arrest at the G2/M phase, downregulation of epithelial-mesenchymal transition (EMT)-related markers, and phosphoinositide 3-kinase/protein kinase B signaling pathways. In this sense, this article reviews data from experimental studies that investigated the links between kaempferol and kaempferol-rich food intake and cancer prevention. Even though growing evidence supports the use of kaempferol for cancer prevention, further preclinical and clinical investigations using kaempferol or kaempferol-rich foods are of pivotal importance before any public health recommendation or formulation using kaempferol.


Metabolism and Pharmacokinetics of Kaempferol
Studies on the in vitro and in vivo pharmacokinetics of kaempferol commonly ingested as high polarity glycosides revealed that this polyphenol is poorly absorbed compared to the aglycones with intermediate polarity [16].
Kaempferol lipophilicity allowed its absorption in the small intestine through passive and facilitated diffusion or active transport [17]. Of note, intake of 14.97 mg kaempferol/day and 27 mg kaempferol from tea resulted in a plasma concentration of 16.69 ng/mL and 15 ng/mL, respectively [18]. The absorbed kaempferol undergoes metabolic transformation to yield the glucuronides and sulfoconjugates forms in the liver [19] and small intestine by intestinal conjugation enzymes [17]. As well, kaempferol and its glycosides are metabolized in the colon by the bacterial microflora that releases the aglycones and broke aglycone C3 ring to form compounds such as 4-methylphenol, phloroglucinol, and 4-hydroxyphenylacetic acid, that are either absorbed and can reach systemic circulation and tissues or be excreted in feces and urine [20][21][22][23][24][25][26][27]. To overcome the low bioavailability of kaempferol, its combination with quercetin increase its bioavailability, consequently improving its bio-efficacy. In fact, studies prove that nanoformulations (e.g., nanoparticles, nanoemulsions, nanoencapsulation) containing kaempferol will be extremely beneficial in improving their bioavailability and consequent efficacy and selectivity for mutated cells, while their effect on normal cells will be limited [28]. Indeed, kaempferol exerts protective effects in non-mutated cells, whereas it triggers apoptosis in those mutated ones. These aspects are mostly linked to the remarkable antioxidant effects of kaempferol, namely acting  The kaempferol reduces the ROS metabolism, cleavage of anti-inflammatory membranes, and disrupts their molecular mechanism as a mechanistic concern to tackle cancer-related expressions (KMF: Kaempferol; Nrf2: Nuclear factor erythroid 2-related factor 2; Keap1: Kelch-like ECH-associated protein 1; RO: Reactive oxygen species).

Anti-Brain Cancer Activity
Glioblastoma is one of the most invasive and aggressive brain tumors, with a very poor prognosis, among other reasons, secondary to the development of resistance against current therapies [55]. It has been reported that Kaempferol inhibited both growth and migration of glioma cells, even when kaempferol was loaded to mucoadhesive nanoemulsion (KPF-MNE) or kaempferol-loaded nanoemulsion (KPF-NE) [55][56][57]. This flavonoid also triggers ROS generation and apoptosis, through

Anti-Brain Cancer Activity
Glioblastoma is one of the most invasive and aggressive brain tumors, with a very poor prognosis, among other reasons, secondary to the development of resistance against current therapies [55]. It has been reported that Kaempferol inhibited both growth and migration of glioma cells, even when kaempferol was loaded to mucoadhesive nanoemulsion (KPF-MNE) or kaempferol-loaded nanoemulsion (KPF-NE) [55][56][57]. This flavonoid also triggers ROS generation and apoptosis, through reduction of the thioredoxin concentrations, superoxide dismutase activity, as well as to increase the levels of pro-inflammatory cytokines (interleukin-6, 8, chemokines, monocyte chemo-attractant protein-1), Bcl-2, cleaved caspase-3, -8, anti-apoptotic proteins survivin and XIAP, cleaved poly(ADP-ribose) polymerase expression, depolarization of mitochondrial membrane potential, and rapid reduction in phosphorylation of ERK and AKT [55,56,58].

Anti-Colon Cancer Activity
Colorectal cancer is amongst the most frequently found cancers worldwide, with more than 1.8 million new cases per year [64]. Kaempferol was reported to possess cytotoxic effects on different human colorectal cancer cells lines, including HCT116, HT-29, HCT-15, LS174-R colon, and SW480 cells [64][65][66].

Anti-Prostate Cancer Activity
Prostate cancer is one of the leading causes of death among man and the need for more effective treatments has driven further research [72]. Kaempferol-3-O-rhamnoside dose-dependently inhibits prostate cancer cells proliferation [72], by upregulating the expression of caspase-8, -9, -3, and poly (ADP-ribose) polymerase proteins [72,73]. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to activate the host immune system and to facilitate host immunosurveillance by the dendritic cells (DC), thereby representing a promising strategy to thwart prostate cancer [73]. Kaempferol has been shown to induce GM-CSF release in PC-3 cells that, in turn, increase the chemotaxis of DC through activation of phospholipase C (PLC), MEK1/2, and protein kinase C (PKC) [73]. Obviously, the transcriptome of prostate cancers cells is also markedly affected by kaempferol treatment as evidenced by the down-regulation of androgen receptor genes expression [74]. In rats, orally administered kaempferol showed no significant toxicity and significantly increased survival, in addition to reducing the growth of PCa xenografts in athymic nude mice [74].

Anti-Bladder Cancer Activity
Bladder cancer is becoming the most common type of cancer of the urinary tract [100]. Kaempferol can strongly and selectively inhibit bladder cancer cells by promoting cell cycle arrest and apoptosis [100][101][102][103]. Also, kaempferol acts by downregulating the PTEN/PI3K/AKT pathway, DNA methyltransferases (DNMT3B), CDK4, CyclinD1, Mcl-1, Bid, and Bcl-xL, and upregulating p53, p38, p21, p-ATM, p-BRCA1, DNA methylation, and Bid and Bax expression [100,102,103]. These in vitro findings were further validated by experiments in subcutaneous xenografted mouse models. Kaempferol significantly suppressed tumor growth as well as cancer metastasis and invasion in xenografted mice with regards to the untreated control compared to the control group mice, and caused downregulation of growth-related markers and c-Met/p38 signaling pathway, yet upregulated apoptosis markers [101].

Anti-Bone Cancer Activity
Kaempferol dose-dependently inhibits the growth of human osteosarcoma cells U-2 OS, 143B, and HOB cells and the migration of human U-2 osteosarcoma (OS) cells with poor toxicity on hFOB cells, a human fetal osteoblast progenitor [109,110]. Kaempferol acts by downregulating the AP-1 DNA binding activity, MMP-2, -9, and urokinase plasminogen activator (uPA) that, in turn, reduces phosphorylated p38, ERK, and JNK [110]. In BALB/c(nu/nu) mice inoculated with human osteosarcoma cells (U-2 OS), kaempferol significantly decreased the number of viable cells and reduced the tumor size [109]. The in vivo anti-bone cancer effects of kaempferol have also been demonstrated in BALB/c(nu/nu) mice inoculated with U-2 OS cells [109].

Conclusions
Cancer accounts among the most overbearing human health problems, relying on chemoprevention approaches as a way to diminish both incidence and mortality. The scrutiny of kaempferol extraordinary list of cancer-fighting properties highlights its full potential. These studies are promising, especially because kaempferol selectively inhibits cancerous cells without affecting healthy ones. In vitro studies unveiled the broad spectrum of kaempferol anticancer targets, including apoptosis, metastasis, inflammation, and angiogenesis. Therefore, cancer cells that often adapt to VEGF inhibition, following treatment with kaempferol, may not escape other detrimental actions induced by this natural flavonoid. Even though kaempferol is questionable as a cancer treatment, it seems to constitute an interesting option when it comes to safety. However, data on the long-term effect of kaempferol intake are scarce. Though kaempferol poor bioavailability represents a significant obstacle, the use of kaempferol-based nanoparticles has brought more hope on cancer chemoprevention strategies. Moreover, most of the research conducted on kaempferol anticancer potency was in vitro, making it difficult to draw a final conclusion on its usefulness. In vivo studies and clinical trials using an exact dose of kaempferol are scarce so far, thus stressing the need for more in-depth experiments varying the dose of kaempferol alone as well as using it with other flavonoids. These data will be of utmost interest to apprehend on kaempferol efficacy in the context of cancer.