Epidemiological studies have revealed that a diet rich in plant-derived foods has a protective effect on human health. Identifying bioactive dietary constituents is an active area of scientific investigation that may lead to new drug discovery. Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many edible plants (e.g. tea, broccoli, cabbage, kale, beans, endive, leek, tomato, strawberries and grapes) and in plants or botanical products commonly used in traditional medicine (e.g. Ginkgo biloba, Tilia spp, Equisetum spp, Moringa oleifera, Sophora japonica and propolis). Some epidemiological studies have found a positive association between the consumption of foods containing kaempferol and a reduced risk of developing several disorders such as cancer and cardiovascular diseases. Numerous preclinical studies have shown that kaempferol and some glycosides of kaempferol have a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anticancer, cardioprotective, neuroprotective, antidiabetic, anti-osteoporotic, estrogenic/antiestrogenic, anxiolytic, analgesic and antiallergic activities. In this article, the distribution of kaempferol in the plant kingdom and its pharmacological properties are reviewed. The pharmacokinetics (e.g. oral bioavailability, metabolism, plasma levels) and safety of kaempferol are also analyzed. This information may help understand the health benefits of kaempferol-containing plants and may contribute to develop this flavonoid as a possible agent for the prevention and treatment of some diseases.

A review on the dietary flavonoid kaempferol.

Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.

Targeting IAP proteins for therapeutic intervention in cancer

Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed “Let food be thy medicine and medicine be thy food.” Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, γ-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed.

/pdf/regulation-of-survival-proliferation-invasion-angiogenesis-1n4kub8nvm.pdf

Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals

G protein-coupled receptors (GPCRs) belong to a superfamily of cell surface signalling proteins that have a pivotal role in many physiological functions and in multiple diseases, including the development of cancer and cancer metastasis. Current drugs that target GPCRs - many of which have excellent therapeutic benefits - are directed towards only a few GPCR members. Therefore, huge efforts are currently underway to develop new GPCR-based drugs, particularly for cancer. We review recent findings that present unexpected opportunities to interfere with major tumorigenic signals by manipulating GPCR-mediated pathways. We also discuss current data regarding novel GPCR targets that may provide promising opportunities for drug discovery in cancer prevention and treatment.

G protein-coupled receptors: novel targets for drug discovery in cancer

Artemisia annua is currently the only commercial source of the sesquiterpene lactone artemisinin.Since artemisinin was discovered as the active component of A. annua in early 1970s, hundreds of papers have focused on the anti-parasitic effects of artemisinin and its semi-synthetic analogs dihydroartemisinin, artemether, arteether, and artesunate. Artemisinin per se has not been used in mainstream clinical practice due to its poor bioavailability when compared to its analogs. In the past decade, the work with artemisinin-based compounds has expanded to their anti-cancer properties. Although artemisinin is a major bioactive component present in the traditional Chinese herbal preparations (tea), leaf flavonoids, also present in the tea, have shown a variety of biological activities and may synergize the effects of artemisinin against malaria and cancer. However, only a few studies have focused on the potential synergistic effects between flavonoids and artemisinin. The resurgent idea that multi-component drug therapy might be better than monotherapy is illustrated by the recent resolution of the World Health Organization to support artemisinin-based combination therapies (ACT), instead of the previously used monotherapy with artemisinins. In this critical review we will discuss the possibility that artemisinin and its semi-synthetic analogs might become more effective to treat parasitic diseases (such as malaria) and cancer if simultaneously delivered with flavonoids. The flavonoids present in A. annua leaves have been linked to suppression of CYP450 enzymes responsible for altering the absorption and metabolism of artemisinin in the body, but also have been linked to a beneficial immunomodulatory activity in subjects afflicted with parasitic and chronic diseases.

https://www.mdpi.com/1420-3049/15/5/3135/pdf

Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer.

The flavonoid quercetin has been reported to inhibit the proliferation of cancer cells, whereas it has no effect on nonneoplastic cells. U87-MG, U251, A172, LN229, and U373 malignant glioma cells were treated with quercetin (50–200 μM). Quercetin did not cause cytotoxicity 24 h after treatment. Combining quercetin with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) strongly augmented TRAIL-mediated apoptosis in U87-MG, U251, A172, and LN229 glioma cells; U373 cells could not be sensitized by quercetin to TRAIL-mediated apoptosis. TRAIL-induced apoptosis was enhanced by quercetin-induced reduction of survivin protein levels. Upon treatment with quercetin, the protein level of survivin was strongly suppressed in U87-MG, U251, and A172 but not in U373 glioma cells. Quercetin exposure resulted in proteasomal degradation of survivin. TRAIL-quercetin–induced apoptosis was markedly reduced by overexpression of survivin. In addition, upon treatment with quercetin, downregulation of survivin was also regulated by the Akt pathway. Taken together, the results of the present study suggest that quercetin sensitizes glioma cells to death-receptor–mediated apoptosis by suppression of inhibitor of the apoptosis protein survivin.

/pdf/quercetin-promotes-degradation-of-survivin-and-thereby-3wp2k2l3hc.pdf

Quercetin promotes degradation of survivin and thereby enhances death-receptor–mediated apoptosis in glioma cells

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a promising cancer drug. However, many tumours are resistant to TRAIL-based therapies. Glioma cells with stem cell features (SCG), such as CD133 expression and neurosphere formation, have been recently identified to be more resistant to cytotoxic drugs than glioma cells lacking stem-cell-like features (NSCGs). Here we report that SCGs are completely resistant to 100-2,000 ng/ml TRAIL, whereas NSCGs revealed a moderate sensitivity to TRAIL. We found that SCGs exhibited only low levels of caspase-8 mRNA and protein, known to be indispensable for TRAIL-induced apoptosis. In addition, we detected hypermethylation of CASP8 promoter in SCGs, whereas NSCGs exhibited a non-methylated CASP8 promoter. Reexpression of caspase-8 by 5-Aza-2'-deoxycytidine was not sufficient to restore TRAIL sensitivity in SCGs cells, suggesting that additional factors cause TRAIL resistance in SCGs. Our data suggest that therapy with TRAIL, either as monotherapy or in combination with demethylating agents, is not effective in treating glioblastoma because SCGs are not targeted by such treatment.

Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation

Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) limits its potential as a drug for cancer therapy. Here, we report that kaempferol, a bioactive plant flavonoid, sensitizes U251 and U87 glioma cells to TRAIL-mediated apoptosis. In contrast, U373 cells are not affected by kaempferol treatment. Treatment of kaempferol alone for 24 h did not induce apoptosis in the cell lines. We provide evidence that TRAIL-induced apoptosis is partially driven by kaempferol-mediated reduction of survivin protein levels. On kaempferol treatment, proteasomal degradation of survivin was observed. Inhibition of proteasomal degradation with MG132 in kaempferol-treated cells restored survivin protein levels in both glial cell lines. Consequently, overexpression of survivin attenuated TRAIL-kaempferol-induced apoptosis. In addition, we show that kaempferol mediates down-regulation of phosphorylated Akt, thereby further reducing survivin protein level. Furthermore, the blockage of the serine/threonine kinase Akt activity by kaempferol is important for inhibition of survivin because active phosphorylated Akt enhances the stability of survivin. However, we also show that the combined treatment of TRAIL and kaempferol induces cleavage (activation) of caspase-8, thereby exerting a proapoptotic effect independent of survivin known not to inhibit caspase-8 activation. Other effects induced by kaempferol were suppression of X-linked inhibitor of apoptosis proteins as the antiapoptotic members of the Bcl-2 family, Bcl-2, Bcl-xL, and Mcl-1 in a concentration-dependent manner. In summary, we showed that suppression of survivin is an essential mechanism in TRAIL-kaempferol-mediated apoptosis.

https://mct.aacrjournals.org/content/molcanther/7/11/3566.full.pdf

Markus David Siegelin

Papers

Quercetin promotes degradation of survivin and thereby enhances death-receptor–mediated apoptosis in glioma cells

Stem-cell-like glioma cells are resistant to TRAIL/Apo2L and exhibit down-regulation of caspase-8 by promoter methylation

The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin

The XIAP inhibitor Embelin enhances TRAIL-mediated apoptosis in malignant glioma cells by down-regulation of the short isoform of FLIP

17-AAG sensitized malignant glioma cells to death-receptor mediated apoptosis.