Natural Compounds and Derivatives As Ser/Thr Protein Kinase Modulators and Inhibitors

pharmaceuticals

Review Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors

Barbara Guerra * and Olaf-Georg Issinger * Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark * Correspondence: [email protected] (B.G.); [email protected] (O.-G.I.); Tel.: +45-6550-2388 (B.G.)



Received: 15 November 2018; Accepted: 17 December 2018; Published: 1 January 2019


Abstract: The need for new drugs is compelling, irrespective of the disease. Focusing on medical problems in the Western countries, heart disease and cancer are at the moment predominant illnesses. Owing to the fact that ~90% of all 21,000 cellular proteins in humans are regulated by phosphorylation/dephosphorylation it is not surprising that the enzymes catalysing these reactions (i.e., protein kinases and phosphatases, respectively) have attracted considerable attention in the recent past. Protein kinases are major team players in cell signalling. In tumours, these enzymes are found to be mutated disturbing the proper function of signalling pathways and leading to uncontrolled cellular growth and sustained malignant behaviour. Hence, the search for small-molecule inhibitors targeting the altered protein kinase molecules in tumour cells has become a major research focus in the academia and pharmaceutical companies.

Keywords: protein kinase; cancer; phosphorylation; natural compounds; flavonoids; kinase inhibition; cellular signalling

1. Introduction The search for anticancer agents from plant sources goes back to the 1950s with the discovery and development of the vinca alkaloids—vinblastine and vincristine—and the isolation of the cytotoxic podophyllotoxins [1]. From the 1940s to the end of 2014, one-hundred-and-seventy-five small molecule inhibitors were approved for treatment of cancer. One-hundred-and-thirty-one are non-synthetic, with 85 being either natural products or directly derived there from [2]. As early as 1982 it was shown that quercetin and related polyphenols selectively inhibited protein kinase CK2 in contrast to PKA that was not affected [3]. Graziani et al. [4] showed that quercetin inhibited the phosphotransferase activity of the Rous sarcoma virus gene product, pp60src. The bacterial alkaloid staurosporine was shown to inhibit PKC in the nanomolar range [5]. Thirty-five years ago the inhibitory efficacy of bioflavonoids and other natural products on certain protein kinases was established, albeit as an interesting tool in the biochemical characterization of the different types of protein kinases in whole cell extracts. The importance of natural compounds and their effect on protein kinases with respect to inhibition of tumour growth came, understandably, to the attention of the medical community much later. Currently, the Food and Drug Administration (FDA) has approved over 40 drugs including orally effective compounds directed against protein kinases, that target a limited number of these enzymes (http://www.brimr.org/PKI/PKIs.htm,[6]). Approximately 150 kinase-targeted drugs are currently in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. It is of interest to note that kinase inhibitors have a wide range of possible targets. Some approved antitumour-directed kinase inhibitors have a very large number of “targets” in the human kinome. Hence, it is not surprising that kinase inhibitors may also affect other signalling molecules relevant in other diseases.

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2. Protein Kinases Protein kinases represent a broad group of evolutionary- and structurally-related enzymes. They preferably catalyse the phosphorylation of serine/threonine and tyrosine residues in their substrates. These hydroxy/phenolic amino acids are embedded in a short recognition sequence of amino acids typical for protein kinases. With a group size of 518 individual members, the “kinome”, that is the sum of all kinase-coding genes, constitutes ~2% of the human genome [7]. Since the isolation of the first serine/threonine-specific kinase (STK) in the muscle in 1959, it took another 20 years until tyrosine protein kinases were discovered. Although all these enzymes differ in size, substrate specificity, mechanism of activation, subunit composition and subcellular localization, they all share a highly conserved homologous catalytic core [8]. Most protein kinases target both serine and threonine (serine/threonine kinases, STKs) residues, others act on tyrosine (tyrosine kinases, TKs) and a number phosphorylate all three types of amino acids (i.e., dual-specificity kinases, DSKs) [9]. The kinome is organised in the following subfamilies of protein kinases, i.e., AGC, CaMK, CK1, CMGC, STE, TK and TKL [10]. The first estimates were that ~30% of all proteins become phosphorylated, however, recent studies suggest that 90% of the 21,000 proteins encoded by the human genome are subjected to this type of post-translational modifications [11]. Phosphatases are enzymes reversing the phosphorylation state of proteins. Currently there are approximately 226 known protein phosphatases [12]. The process of phosphorylation and dephosphorylation can be extremely complex, since a single kinase or phosphatase may simultaneously have multiple substrates and may function in various cell-signalling pathways. The concept of reversible protein phosphorylation developed by Fischer and Krebs with the elucidation of the hormonal control of glycogenolysis [13] is the basis for the understanding of how cellular functions are controlled, a finding that brought E.G Krebs and E. Fischer the Nobel Prize in Medicine in 1992.

3. Protein Kinases in Cellular Signalling The signalling pathways regulated by protein kinases contribute to the onset and progression of almost all types of cancer. Consequently, research of the signalling pathways mediated by protein kinases and the possibility of blocking them with targeted treatment does have major clinical/therapeutic utility especially since many of these proteins act as oncogenes. The signalling networks operating in cancer cells can also contribute to innate or acquired resistance to treatment, since they are able to create the most common or rare oncogenic mutations different from tumour to tumour (i.e., the so-called polygenic tumour biology, [14,15]). Most cancer-relevant natural products interact with molecules involved in key intracellular signalling pathways like PI3K/AKT/mTOR/GSK3β, Ras/Raf/MEK/MAPK/ERK1/2, PL-Cγ/PKC/ CaMKII/IV or JNK just to mention the classical signalling cascades. They all have in common that they influence key molecules in the nucleus mostly proteins involved in the regulation of gene transcription. Yet, these transcription factors are also subject to interaction with small natural compounds. Most molecules in the signalling pathways shown in Figure1 belong to the STK group. Their activation, however, occurs following stimulation of tyrosine kinase receptors located in the cell plasma membrane and become active by their binding of external ligands on the extracellular domain of the receptor molecule (Figure1). Pharmaceuticals 2019, 12, 4 3 of 21 Pharmaceuticals 2019, 14, 4 3 of 21

Figure 1. 1. Schematic representation of intracellular signal transduction transduction pathways supporting supporting cell cell proliferationproliferation andand survival. survival. Activation Activation of of the the PI3K/AKT/mTOR, PI3K/AKT/mTOR, RAS/Raf/MEK/ERK RAS/Raf/MEK/ERK andand IKK/NF-IKK/NF-κBκB pathwayspathways occurs following a stimulus represented by a a ligand, ligand, which which binds binds a a receptor receptor tyrosine tyrosine kinase located on the plasma plasma membrane. membrane. These These pathways pathways control control gene gene expression expression in ina number a number of ofways ways comprising comprising phosphorylation phosphorylation of oftranscription transcription factors factors and and co-factors co-factors and and modification modification of ofprotein-binding protein-binding DNA. DNA. R: Receptor; R: Receptor; PTEN: PTEN: phosphatase phosphatase and tensin and homolog; tensin homolog; IRS: insulin IRS: receptor insulin receptorsubstrate; substrate; PI3K: phosphatidylinositol-3-kinase; PI3K: phosphatidylinositol-3-kinase; PDK1: PDK1: phosphoinositide-dependent-kinase-1; phosphoinositide-dependent-kinase-1; CK2: CK2:protein protein kinase kinase CK2; CK2;AKT: AKT: protein protein kinase kinase B; GSK3β: B; GSK3 glycogenβ: glycogen synthase synthase kinase kinase 3; FRAP/mTOR: 3; FRAP/mTOR: 12- 12-rapamycin-associatedrapamycin-associated protein protein 1/mammalian 1/mammalian target target of of rapamycin; rapamycin; GβL: GβL: G G protein protein beta beta subunit-like; GRB: growth growth factor factor receptor-bound receptor-bound protein protein 2; 2; SOS: SOS: son son of of sevenless; sevenless; Raf: Raf: rapidly rapidly accelerated accelerated fibrosarcoma;fibrosarcoma; PKC: protein kinase kinase C; C; MEK: MEK: mitogen-activated mitogen-activated protein protein kinase; kinase; ERK: ERK: extracellular extracellular signal-regulatedsignal-regulated kinase; kinase; CAMKII/IV: CAMKII/IV: calcium-calmodulin kinase II/IV; p90RSK: p90RSK: p90 ribosomal s6 s6 kinase; IKK IKKα:α:I κ IκBB kinase kinaseα -subunit; α-subunit; IKK IKKβ:β:Iκ B IκB kinase kinaseβ-subunit; β-subunit; NF- κ NF-κB:B: nuclear nuclear factor-kappa factor-kappa B; IκB α B;: inhibitorIκBα: inhibitor of kappa of B; kappa AP-1: activator B; AP-1: protein-1; activator CREB: protein-1; cAMP CREB: response cAMP element-binding response element-binding protein. protein.

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4. Role of Protein Kinases in Cancer As already mentioned, protein kinases recognise specific short amino acid sequences in their substrates [16]. Some protein substrates, like the well-characterised tumour suppressor p53 protein is targeted by more than 30 different protein kinases and at more than 20 sites. Some sites, e.g., Ser15, are phosphorylated by more than eight different protein kinases. Needless to say that the elucidation of which protein kinase is responsible for the phosphorylation at a particular site at a certain time point is a challenging task [17]. The interesting aspect of these considerations is that many proteins involved in signal transduction are targets for protein kinase modification and, most importantly, their function and/or activity can be modified rapidly, without the need of genetic alterations. The process of phosphorylation/dephosphorylation is a very efficient and rapid way of altering the activity of signalling molecules and one can imagine that mutations of either protein kinases or substrate molecules may lead to aberrations in signalling pathways important for preserving normal cellular homeostasis. The initial causes of cancer are multiple, including prolonged hormone stimulation (e.g., oestrogens in breast cancers and androgens in prostate cancers), viruses, chemical carcinogens, radiation, persistent inflammation, acquired or inborn genetic events and aneuploidy. Cancer is regarded as a genetic disease involving oncogenes activated by amplification or by point mutations. Chromosomal aberrations, which result in alterations in oncogenes and tumour suppressor genes in somatic cells, are another possible cause leading to cancer induction in humans and experimental animals (Figure2). The abnormal oncogenic activation of protein kinases derives from multiple types of genetic changes. These alterations result in increased specific activity of the kinases themselves, their overexpression, or the loss of negative regulation. Most frequently, cancer cells harbour somatic point mutations at structurally conserved residues, or mutation in hotspot regions, which constitutively upregulate the kinase activity [18]. In addition, genomic instability—a hallmark of cancer cell [19,20]—can also result in elevated kinase activity enhancing intracellular signalling through a number of distinct mechanisms. Defects in the surveillance pathways that maintain genomic integrity can produce amplifications of large chromosomal regions or complex chromosomal rearrangements, which in turn result in a defect expression of a protein kinase or the expression of a constitutively activated chimeric form. The abnormal oncogenic activation of protein kinases can also derive from multiple epigenetic [21,22], transcriptional or post-transcriptional changes as a result from alternative splicing regulation and miRNA expression (Figure2,[9]). The original idea of a ‘magic bullet’ to cure cancer that is the design of drugs that directly target the intended cell component has been largely abandoned. Mounting evidence suggests that signalling pathways that become dysfunctional by altered molecules should be tackled by combination therapy including multiple kinase inhibitors [23]. There are various mechanisms by which kinase inhibitors bind to their target kinases broadly classified into kinase inhibitors that bind covalently or noncovalently to or around the ATP binding site. Primarily, protein kinases interact with ATP through a cleft located between the N- and C-terminal lobes of the kinase domain. However, specific tumour genetics, tumour microenvironment, drug resistance and pharmacogenomics determine how effective a compound will be in the treatment of a specific cancer. The signalling pathways in cells in a given organism are unique and detailed knowledge on their components can be used to find drugs to influence them based on the diseases that should be tackled. In other words a drug that was designed to treat, for instance, cancer also can have a positive effect on diabetes. These observations led to a more holistic insight concerning treatment of various major diseases. The concept of this review is to give place for a complementary therapeutic research approach, based on one hand on western medicine and on the other hand on knowledge from traditional Chinese medicine (TCM). Pharmaceuticals 2019, 12, 4 5 of 21 Pharmaceuticals 2019, 14, 4 5 of 21

FigureFigure 2. 2.Possible Possible alterations alterationsof ofprotein protein kinase-codingkinase-coding genes and and their their outcome. outcome. (A (A) Point) Point mutations mutations areare capable capable of of activating activating aa proto-oncogeneproto-oncogene product resulting resulting in in the the expression expression of of a aconstitutively constitutively activeactive protein protein kinase.kinase. ( BB)) In In addition addition to tonucleotide nucleotide substitution, substitution, gene geneamplification amplification that results that resultsfrom fromamplification amplification of chromosomal of chromosomal fragments fragments can result can result in aberrant in aberrant expression expression of genes of genes coding coding for forprotein protein kinases. kinases. This This can can result result in uncontrolled in uncontrolled activation activation of signalling of signalling pathways pathways controlled controlled by the by theoverexpressed overexpressed protein protein kinases. kinases. (C) ( C Alteration) Alteration in in the the structure structure of of chromosomes chromosomes can can take take several several formsforms including including translocation, translocation, inversion, inversion, deletion deletion and insertion of of genetic genetic material. material. Chromosome Chromosome abnormalitiesabnormalities can can result result in the in expression the expression of higher of higher levels of levels a protein, of a chimericprotein, chimerichyperactive hyperactive proteins or lossproteins of tumour or loss suppressor of tumour gene suppressor products. gene products.

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5. Natural Bioactive Compounds as Kinase Inhibitors There is evidence that the medicinal use of natural products derived from sources such as plants, animals or microorganisms dates back to the Neanderthal period [24,25]. Owing to the diverse biological activities of the isolated natural products all major civilizations have accumulated knowledge and experience in their application. During the 19th century modern Western chemistry succeeded in the identification of the active ingredients from natural sources leading to the isolation, for instance, of morphine, salicin, emetine strychnine, colchicine, caffeine, nicotine, cocaine, etc. Moreover, the elucidation of their molecular structure allowed the synthesis of the desired compounds instead of isolating them from natural sources [26]. This procedure also had the advantage to be cheaper and, moreover, allowed to use the active ingredient of a medicinal plant and not the crude plant extract. Newman [27] estimates that ~60% of the drugs that are nowadays available—including household names such as artemisinin, camptothecin, lovastatin, maytansine, paclitaxel, penicillin, reserpine and silibinin—were either directly or indirectly derived from natural products. Plants provide an extensive reservoir of natural products. The significance of natural products in health care is supported by a report that 80% of the global population still relies on plant-derived medicines to address their health care needs. In recent years, there has been a major paradigm shift in discovery and screening of natural products as potential kinase inhibitors. Protein kinase inhibitors belong chemically to a variety of plant compounds such as flavonoids, alkaloids, sesquiterpenes, diterpenoids and polyphenolics, which represent a large and diverse group of naturally occurring compounds found in a variety of fruits, vegetables and medicinal plants with various anticancer properties. In contrast to TCM, the Western approach is more specific and targeted, although one has to admit that the “magic bullet” that has never been found, and probably will not be found, simply because cancer is a complex genetic disease. Danggui Longhui Wan (DLW) is a typical traditional Chinese medicinal prescription for the treatment of chronic myeloid leukaemia (CML) [28,29]. It is made up of 11 herbal medicines. The search for the active compound revealed that only indirubin was effective against CML. The remaining 10 compounds were all inactive. Indirubin was identified as the active ingredient [28]. Indirubin and its analogues are potent inhibitors of cyclin-dependent kinases (CDKs) involved in cell division [30]. Since tumour cells heavily depend on cell division, the inhibition of CDKs will block progression of cell division and so tumour growth. However, indirubin worked well in cell-free tests but proved difficult to be absorbed in the intestinal tract. We will let this stand as one example, where the analysis of TCM can be rewarding to identify the active compound(s). Once identified, they can be further “improved” by chemical modifications. However, as in the case of DLW, one should not dismiss the other ten compounds as useless. Quite the contrary, especially, since the mixture has worked successfully in treating CML in the last two thousand or more years. One can imagine that there are compounds present in the mixture, which might increase the solubility of the active components that by themselves are insoluble. Therefore, TCM that is based on herb mixtures could be a role model for finding an active ingredient and together with complementary compounds it would finally make it a magic bullet.

6. Classification of Flavonoids and Other Polyphenolic Compounds Polyphenols have been credited with their antioxidant properties targeting protein kinases in general through interaction with the ATP-binding site. Lolli et al. [31] have crystallised different flavonoids together with protein kinase CK2α. The authors showed that apigenin and luteolin, when modelled into the CK1 delta isoform were fitting well. This fit could apply for many other kinases. Baier et al. [32,33] modelled two CK2 isoforms with different flavonoid compounds. Their results support the notion that the tested flavonoids are purely ATP competitive. Especially, apigenin, which is a relative simple flavonoid, could be a role model for other flavonoids. Thirty-four PDB entries correspond to more than 2000 kinase and more than 150 flavonoid entries (one should keep in mind that in these PDB entries the host protein is not necessarily a protein kinase). Pharmaceuticals 2019, 14, 4 7 of 21 Pharmaceuticals 2019, 1214, 4 7 of 21

In summary we can say that protein kinases can be inhibited by flavonoids through ATP competitiveIn summary inhibition. we can This say is because that protein of the kinases molecular can basic be inhibited structure by of flavonoidsflavonoids throughthat fits ATPwell intocompetitive the ATP inhibition. binding This pocket isbecause and the of neighbouring the molecular basic hinge structure region, ofwhich flavonoids provides that H-bonds fits well into for interactions,the ATP binding yet, pocketthis interaction and the neighbouringmay not apply hinge to all region, flavonoids. which provides H-bonds for interactions, yet, thisPolyphenols interaction comprise may not apply a wide to varietyall flavonoids. of molecules that have a polyphenol structure, i.e., severalPolyphenols hydroxyl groups comprise on a aromatic wide variety rings, of but molecules also molecules that have with a polyphenol one phenol structure, ring. Polyphenols i.e., several arehydroxyl subdivided groups into on several aromatic major rings, subclasses: but also phenolic molecules acids, with stilbenes, one phenol tannins, ring. diferuloylmethanes Polyphenols are andsubdivided flavonoids. into several There are major six subclasses: major subgroups phenolic of acids, flavonoids. stilbenes, They tannins, are the diferuloylmethanes most abundant antioxidantsand flavonoids. in our There diet are and six majorare common subgroups constituents of flavonoids. of foods They of are plant the origin most abundant and are wide antioxidants spread constituentsin our diet and of arefruits, common vegetables, constituents cereal, ofolive, foods dry of plantlegumes, origin chocolate and are and wide beverages spread constituents such as tea, of coffeefruits, vegetables,and wine [34]. cereal, Inhibition olive, dry of legumes, cell growth, chocolate antiapoptotic and beverages properties, such as inhibition tea, coffee of and tumour wine [cell34]. invasionInhibition and of cell inhibition growth, antiapoptotic of protein kinase properties, activities inhibition are part of tumour of the cell antitumour invasion and activities inhibition of flavonoids.of protein kinase It is interesting activities areto note part that of the bioflavonoids antitumour are activities by far ofthe flavonoids. largest natural It is interestingcompound togroup note inhibitingthat bioflavonoids protein kinases. are by far In the 1994 largest more natural than 500 compound types of groupflavonoids inhibiting were proteinreported kinases. [35]. Now, In 1994 24 yearsmore later, than 500the typesnumber of has flavonoids grown to were ~9000 reported [36]. Flavones [35]. Now, and 24 flavonols years later, contain the numberthe largest has number grown ofto ~9000compounds [36]. Flavones within the and group flavonols of bioflavonoids. contain the largest We are number presenting of compounds here only within a selection the group of the of mostbioflavonoids. described We members are presenting of the flavonoid here only afamily selection and of other the mostpolyphenol described compounds members ofwith the respect flavonoid to theirfamily effect and on other protein polyphenol kinases compounds and cancer. with respect to their effect on protein kinases and cancer. Flavones Flavones

Apigenin is a flavone present in vegetables such as parsley, celery and chamomile [37]. It acts Apigenin is aa flavoneflavone presentpresent inin vegetables vegetables such such as as parsley, parsley, celery celery and and chamomile chamomile [37 [37].]. It actsIt acts as as an effective anticancer natural product on TRAIL, WNT/β-catenin signalling, the JAK-STAT asan effectivean effective anticancer anticancer natural natural product product on TRAIL, on TRAIL, WNT/ βWNT/β-catenin-catenin signalling, signalling, the JAK-STAT the JAK-STAT pathway pathway and microRNAs. Moreover, it was shown that it targets the PI3K/AKT/mTOR signalling pathwayand microRNAs. and microRNAs. Moreover, Moreover, it was shown it was that shown it targets that it the targets PI3K/AKT/mTOR the PI3K/AKT/mTOR signalling signalling axis for axis for cancer prevention [38]. axiscancer for prevention cancer prevention [38]. [38]. Apigenin also has been shown to inhibit prostate cancer progression in TRAMP mice by Apigenin also has been shown to inhibit prostate cancer progression in TRAMP mice by targeting the PI3K/AKT/FoxO pathway [39], block IKKalpha activation and suppress prostate targeting the the PI3K/AKT/FoxO PI3K/AKT/FoxO pathway pathway [ 39 [39],], block block IKKalpha IKKalpha activation activation and suppress and suppress prostate prostate cancer cancer progression [40]. cancerprogression progression [40]. [40]. Luteolin is a type of flavonoid that inhibits proliferation involving MAPK and mTOR Luteolin is is a atype type of flavonoid of flavonoid that inhibits that inhibits proliferation proliferation involving involving MAPK and MAPK mTOR and signalling mTOR signalling pathways in various tumour cell lines [41]. signallingpathways inpathways various in tumour various cell tumour lines [ 41cell]. lines [41]. Baicalein is another flavone targeting prosurvival signalling pathways. It is one of the major Baicalein is another flavone flavone targeting prosurvival signalling pathways pathways.. It It is is one one of the major active constituents of Scutellariae radix. In TCM it is known as Huang Qin and used to treat various active constituents of Scutellariae radix radix.. In In TCM TCM it it is is known known as as Huang Huang Qin Qin and and used used to treat various diseases. The antitumour effects of baicalein are mainly due to its ability to inhibit cyclin-containing diseases. The The antitumour effects effects of baicalein are mainly due to its ability to inhibit cyclin-containing complexes involved in cell cycle regulation, to scavenge oxidative radicals and to attenuate mitogen complexes involved in cell cycle regulation, to scavenge oxidative radicals and to attenuate mitogen activated protein kinase (MAPK), AKT and mTOR activity [42]. activated protein kinase (MAPK), AKT and mTOR activity [[42].42]. Most of the flavones listed in Table 1 share similar targets as described for apigenin. Most of the flavones flavones listed in Table1 1 share share similar similar targets targets as as described described for for apigenin. apigenin.

Flavonols

Quercetin has been found in apples, berries, red onions, cherries, broccoli, coriander, etc. [43] Quercetin has been found in apples, berries, red onions, cherries, broccoli, coriander, etc. [43]. Beside TKs, it has been shown to inhibit the serine/threonine kinases, AKT, mTOR, MAPK, ERK1/2, Beside TKs, it has been shown to inhibit the serine/threonine kinases, AKT, mTOR, MAPK, ERK1/2, JNK, etc. This indicates that this compound inhibits members of major pro-survival signalling JNK, etc. This indicates that this compound inhibits members of major pro-survival signalling pathways as shown in Figure 1. A linked search for the number of citations found for quercetin, protein kinases and cancer amounted to 344.

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Pharmaceuticals 2019, 14, 4 8 of 21 Pharmaceuticalspathways as 20192019 shown,, 1414,, 44 in Figure1. A linked search for the number of citations found for quercetin, 8 8 ofof 2121 proteinKaempferol. kinases and Common cancer amountedfoods that to contain 344. kaempferol include apples, grapes, tomatoes, green tea, potatoes,Kaempferol. onions CommonCommon and broccoli, foodsfoods that thatjust contain containto name kaempferol kaempferol a few fruits include include and apples,vegetables. apples, grapes, grapes, Kaempferol tomatoes, tomatoes,tomatoes, has green greengreenbeen tea, showntea,potatoes,tea, potatoes,potatoes, to onionsinhibit onionsonions andangiogenesis broccoli, andand broccoli, just by totargeting just name to aname fewVEGF fruitsa fewreceptor-2 and fruits vegetables. andand vegetables.down-regulating Kaempferol Kaempferol has the been PI3K/AKT, shownhas been to MEKshowninhibitshown and angiogenesistoto inhibitinhibit ERK pathways angiogenesisangiogenesis by targeting [44]. byby VEGF Moreover, targetingtargeting receptor-2 kaempferolVEGFVEGF and receptor-2receptor-2 down-regulating inhibits andand invasion down-regulatingdown-regulating the PI3K/AKT, and migration thethe MEK PI3K/AKT,PI3K/AKT, andof renal ERK cancerMEKpathways and cells [44 ERK through]. Moreover, pathways the downregulation kaempferol [44]. Moreover, inhibits of AKT kaempferol invasion and FAK and inhibits migrationpathways invasion of[45] renal and and cancer it increases migration cells through apoptosis of renal the incancerdownregulation human cells cervical through of cancer AKT the downregulation andHeLa FAK cells pathways via the of PI3K/AKTAKT [45] andand it FAKand increases hTERTpathways apoptosis pathways [45] and in [46]. human it increases cervical apoptosis cancer inHeLain humanhumanFisetin cells cervicalcervical via has the been PI3K/AKTcancercancer found HeLaHeLa in and cellscells strawberries, hTERT viavia thethe pathways PI3K/AKTPI3K/AKT apples, [46 persimmons,andand]. hTERThTERT pathwayspathways onions and [46].[46]. cucumbers. It has shownFisetin anticancer has has been been activity found found on in in strawberries, mammary strawberries, carcinoma apples, apples, persimmons, cells persimmons, via regulation onions onions and of cucumbers. and the cucumbers. PI3K/AKT/mTOR It has shown It has pathwayshownanticancershown anticancer anticancer [47]. activity It inhibits on activity activity mammary laryngeal on on mammary mammary carcinoma carcinoma carcinoma carcinomacells through via regulation cellsregulation cells via via of regulationregulation theof AKT/NF-κB/mTOR PI3K/AKT/mTOR of of the the PI3K/AKT/mTOR PI3K/AKT/mTOR pathwayand ERK1/2 [47]. signallingpathwayIt inhibits [47]. cascades laryngeal It inhibits [48] carcinoma Moreover,laryngeal through carcinomait has regulationbeen through shown of thatregulation AKT/NF- fisetin κ ofinducesB/mTOR AKT/NF-κB/mTOR apoptosis and ERK1/2 in human and signalling ERK1/2 non- smallsignallingcascadessignalling cell [lung 48 cascadescascades] Moreover, cancer [48][48] through itMoreover,Moreover, has beeninhibition shownitit hashas of beenbeen that the fisetin shownMAPKshown induces thatsignallingthat fisetinfisetin apoptosis cascade inducesinduces in [49]. human apoptosisapoptosis non-small inin humanhuman cell non-non- lung smallcancersmall cellcell through lunglung cancercancer inhibition throughthrough of the inhibitioninhibition MAPK signalling ofof thethe MAPKMAPK cascade signallingsignalling [49]. cascadecascade [49].[49]. Flavanones Flavanones

Naringenin. Almost exclusively found in citrus fruits, especially in grapefruit. Cytotoxicity has Naringenin. Almost exclusively found in citrus fruits, especially in grapefruit. Cytotoxicity has been Naringenin.induced by naringeninAlmost exclusively in cancer found cells infrom citrus breast, fruits, stomach, especially liver, in grapefruit.cervix, pancreas Cytotoxicity and colon has been induced by naringenin in cancer cells from breast, stomach, liver, cervix, pancreas and colon tissues,been induced along with by naringenin leukaemia in cells. cancer Naringenin cells from has breast, been stomach, shown to liver, induce cervix, cell pancreas death in and prostate colon tissues, along with leukaemia cells. Naringenin has been shown to induce cell death in prostate cancertissues, cells alongalong via withwith PI3K/AKT leukaemia leukaemia and cells. MAPKcells. Naringenin Naringenin signalling has haspathways been been shown shown[50]. to induceMoreover, to induce cell deathit cell was death in shown prostate in thatprostate cancer this cancer cells via PI3K/AKT and MAPK signalling pathways [50]. Moreover, it was shown that this compoundcellscancer via cells PI3K/AKT inhibitsvia PI3K/AKT and cell MAPK proliferation,and signallingMAPK signalling pathways migration pathways [ 50 and]. Moreover, invasion [50]. Moreover, it was in shown gastric it was that cancer shown this compound cellsthat this by compound inhibits cell proliferation, migration and invasion in gastric cancer cells by downregulationinhibitscompound cell proliferation, inhibits of the cellAKT migration proliferation,pathway and [51]. invasion migration in gastric and cancer invasion cells by in downregulation gastric cancer of cells the AKT by downregulation of the AKT pathway [51]. pathwaydownregulation [51]. of the AKT pathway [51]. Flavanonols Flavanonols

Silibinin. Silymarin, which is extracted from the seeds and fruits of the milk thistle Silybum marianumSilibinin. is a Silymarin, mixture of which three is structural extracted isomers, from the silibinin, seeds and silidianin fruits of and the silichristin. milk thistle SilibininSilybum Silibinin. Silymarin, which is extracted from the seeds and fruits of the milk thistle Silybum inducesmarianum cell is is cycle a a mixture mixture arrest of of in three three G1 phase, structural structural apoptosis isomers, isomers, and silibinin, silibinin, JNK/SAPK silidianin silidianin upregulation and and silichristin. silichristin. in SW1990 Silibinin Silibinin human marianum is a mixture of three structural isomers, silibinin, silidianin and silichristin. Silibinin induces pancreaticinducesinduces cell cell cancer cycle cycle cells arrest arrest [52]. in in Moreover, G1 G1 phase, phase, it apoptosis apoptosis was shown and and that JNK/SAPK JNK/SAPK combined upregulation upregulation treatment with in in SW1990 SW1990 sorafenib human human and cell cycle arrest in G1 phase, apoptosis and JNK/SAPK upregulation in SW1990 human pancreatic silibininpancreatic synergistically cancer cells [52]. targets Moreover, both hepatocellularit was shown that carcinoma combined cells treatment and cancer with stemsorafenib cells and by cancer cells [52]. Moreover, it was shown that combined treatment with sorafenib and silibinin enhancedsilibininsilibinin synergistically synergisticallyinhibition of the targets targets phosphorylation both both hepatocellular hepatocellular of STAT3/ERK/AKT carcinoma carcinoma [53]. cells cells and and cancer cancer stem stem cells cells by by synergistically targets both hepatocellular carcinoma cells and cancer stem cells by enhanced inhibition enhancedTaxifolin. inhibition This compoundof the phosphorylation can be found of STAT3/ERK/AKT in conifers like the [53]. siberian larch, Larix sibirica, in of the phosphorylation of STAT3/ERK/AKT [53]. Russia,Taxifolin. in Pinus Thisroxburghii compound, in Cedrus can deodara be found and in in conifers the Chinese like yew, the siberian Taxus chinensis larch, Larix var. mairei sibirica. It,, inis in Taxifolin. This compound can be found in conifers like the siberian larch, Larix sibirica, in Russia, alsoRussia, found in Pinusin the roxburghii silymarin,, ininextract Cedrus from deodara the milkandand ininthistle thethe ChineseChinese seeds. Taxifolin yew,yew, Taxus inhibits chinensis growth, var. maireimigration.. ItIt isis in Pinus roxburghii, in Cedrus deodara and in the Chinese yew, Taxus chinensis var. mairei. It is also andalso invasionfound in the of human silymarin osteosarcoma extract from cells the milk by reducing thistle seeds. expression Taxifolin levels inhibits of AKT growth, [54]. migration Taxifolin found in the silymarin extract from the milk thistle seeds. Taxifolin inhibits growth, migration and suppressesand invasion UV-induced of human skin osteosarcoma carcinogenesis cells by by targeting reducing EGFR expression and PI3K levels [55]. of AKT [54]. Taxifolin invasion of human osteosarcoma cells by reducing expression levels of AKT [54]. Taxifolin suppresses suppressessuppresses UV-inducedUV-induced skinskin carcinogenesiscarcinogenesis byby targetingtargeting EGFREGFR andand PI3KPI3K [55].[55]. UV-induced skin carcinogenesis by targeting EGFR and PI3K [55]. Isoflavones IsoflavonesIsoflavonesIsoflavones

O O

O O Genistein and daidzein are found in a numberO of plants including lupine, fava beans and soybeans.Genistein Genistein and daidzein reduces are the found activation in a of number AKT ofand plants EGFR, including and the lupine, production fava beans of IL6 and in soybeans.soybeans. Genistein Genistein reduces reduces the the activation activation of of AKT AKT and and EGFR, EGFR, and and the the production production of of IL6 IL6 in in

Pharmaceuticals 2019, 14, 4 9 of 21 Pharmaceuticals 2019, 12, 4 9 of 21 cholangiocarcinomaPharmaceuticals 2019, 14, 4 cells involving oestrogen and oestrogen receptors [56]. Inactivation of AKT, 9 of 21 ERK Genisteinand NF-κB and by daidzein genistein are reduces found inovarian a number carcinoma of plants oncogenicity including lupine, [57]. Moreover, fava beans it and was soybeans. shown cholangiocarcinoma cells involving oestrogen and oestrogen receptors [56]. Inactivation of AKT, thatGenistein genistein reduces inhibits the activationthe growth of AKTand regulates and EGFR, the and migration the production and invasion of IL6 inabilities cholangiocarcinoma of melanoma ERK and NF-κB by genistein reduces ovarian carcinoma oncogenicity [57]. Moreover, it was shown cells involving via the FAK/paxillin oestrogen and and oestrogen MAPK receptors pathways [ 56 [58].]. Inactivation Taking everything of AKT, ERK into and consideration, NF-κB by that genistein inhibits the growth and regulates the migration and invasion abilities of melanoma genistein reduces acts as ovarian a chemotherapeutic carcinoma oncogenicity agent against [57]. different Moreover, types it was of shown cancer, that mainly genistein by altering inhibits cells via the FAK/paxillin and MAPK pathways [58]. Taking everything into consideration, apoptosis,the growth andthe regulates cell cycle the and migration angiogenesis and invasion and inhibiting abilities of metastasis. melanoma cells It appears via the FAK/paxillin so that the genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering therapeuticand MAPK pathwayseffects of genistein [58]. Taking very everything often result into from consideration, targeting extracellular genistein acts signal-regulated as a chemotherapeutic kinase apoptosis, the cell cycle and angiogenesis and inhibiting metastasis. It appears so that the 1/2agent (ERK1/2), against different mitogen-activated types of cancer, protein mainly kinase by (MAPK), altering apoptosis, inhibitor of the NF-κB cell cycle (IκB) and and angiogenesis PI3K/AKT therapeutic effects of genistein very often result from targeting extracellular signal-regulated kinase signallingand inhibiting pathways. metastasis. It appears so that the therapeutic effects of genistein very often result 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB) and PI3K/AKT from targeting extracellular signal-regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinase signalling pathways. (MAPK),Flavan-3-ols/Catechins inhibitor of NF-κB (IκB) and PI3K/AKT signalling pathways. Flavan-3-ols/CatechinsFlavan-3-ols/Catechins O

O OH

R OH Epigallocatechin-3-gallate (EGCG) is found in high content in the dried leaves of green tea, R white tea and in smaller quantities, black tea. EGCG downregulates doxorubicin-induced Epigallocatechin-3-gallate (EGCG) is found in high content in the dried leaves of green tea, overexpressionEpigallocatechin-3-gallate of P-glycoprotein (EGCG) through is found the coordinate in high content inhibition in the of PI3K/AKT dried leaves and of MEK/ERK green tea, whiteEpigallocatechin-3-gallate tea and in smaller quantities, (EGCG) is black found tea. in EGCG high content downregulates in the dried doxorubicin-induced leaves of green signallingwhite tea pathways and in smaller [59]. Moreover, quantities, it was black shown tea. that EGCG the compound downregulates can promote doxorubicin-induced apoptosis in tea,overexpression white tea and of P-glycoprotein in smaller quantities, through black the coordinate tea. EGCG inhibition downregulates of PI3K/AKT doxorubicin-induced and MEK/ERK humanoverexpression breast cancer of P-glycoprotein T47D cells through through the downregulation coordinate inhibition of the PI3K/AKT of PI3K/AKT signalling and MEK/ERK cascade overexpressionsignalling pathways of P-glycoprotein [59]. Moreover, through it was the shown coordinate that the inhibition compound of PI3K/AKT can promote and apoptosis MEK/ERK in [60,61].signalling pathways [59]. Moreover, it was shown that the compound can promote apoptosis in signallinghuman breast pathways cancer [59 ]. T47D Moreover, cells throughit was shown downregulation that the compound of the can PI3K/AKT promote apoptosis signalling in cascade human breast[60,61]. cancer T47D cells through downregulation of the PI3K/AKT signalling cascade [60,61]. Anthocyanins[60,61]. Anthocyanins Anthocyanins

Delphinidin is an anthocyanidin, a primary plant pigment. It is also an antioxidant and can be found in cranberries and concord grapes as well as pomegranates and bilberries. The compound Delphinidin is an anthocyanidin, a primary plant pigment. It is also an antioxidant and can be inducesDelphinidin apoptosis is an and anthocyanidin, inhibits epithelial-to-mesenchymal a primary plant pigment. transition It is also via an antioxidant the ERK/p38 and MAPK- can be found in cranberries and concord grapes as well as pomegranates and bilberries. The compound signallingfound in cranberries pathway andin human concord osteosarcoma grapes as well cell as pomegranates lines [62]. Delphinidin and bilberries. also The influences compound the induces apoptosis and inhibits epithelial-to-mesenchymal transition via the ERK/p38 MAPK- proliferationinduces apoptosis of ovarian and inhibits cancer epithelial-to-mesenchymal cells via PI3K/AKT transition and ERK1/2 via the MAPK ERK/p38 signalling MAPK-signalling axis [63] signalling pathway in human osteosarcoma cell lines [62]. Delphinidin also influences the pathwayMoreover, in it human was shown osteosarcoma that this cell compound lines [62]. Delphinidininduces autophagy also influences in HER2+ the proliferationbreast cancer of cells ovarian via proliferation of ovarian cancer cells via PI3K/AKT and ERK1/2 MAPK signalling axis [63] inhibitioncancer cells of via AKT/mTOR PI3K/AKT pathway and ERK1/2 [64]. MAPK signalling axis [63] Moreover, it was shown that this Moreover, it was shown that this compound induces autophagy in HER2+ breast cancer cells via compoundinhibition of induces AKT/mTOR autophagy pathway in HER2+ [64]. breast cancer cells via inhibition of AKT/mTOR pathway [64]. Sesquiterpenesinhibition of AKT/mTOR pathway [64]. Sesquiterpenes Sesquiterpenes Parthenolide Parthenolide

Parthenolide is a sesquiterpene lactone of the germacranolide class, which occurs naturally in Parthenolide is a sesquiterpene lactone of the germacranolide class, which occurs naturally in the the plant feverfew (Tanacetum parthenium), after which it is named. It is found in highest plantParthenolide feverfew (Tanacetum is a sesquiterpene parthenium lactone), after whichof the itgermacranolide is named. It is class, found which in highest occurs concentration naturally in concentrationParthenolide in the is aflowers sesquiterpene and fruit. lactone Parthenolide of the germacranolide suppresses non-small class, which cell lung occurs cancer naturally GLC-82 in inthe the plant flowers feverfew and fruit. (Tanacetum Parthenolide parthenium suppresses), after non-small which it cell is named.lung cancer It is GLC-82 found cell in growth highest concentration in the flowers and fruit. Parthenolide suppresses non-small cell lung cancer GLC-82

Pharmaceuticals 2019, 14, 4 10 of 21 Pharmaceuticals 2019, 1214, 4 10 of 21 Pharmaceuticals 2019, 14, 4 10 of 21 cell growth via B-Raf/MAPK/ERK pathway [65]. Moreover, it induces apoptosis and autophagy cell growth via B-Raf/MAPK/ERK pathway [65]. Moreover, it induces apoptosis and autophagy cellthrough growth the suppression via B-Raf/MAPK/ERK of PI3K/AKT pathway signalling [65]. cascade Moreover, in cervical it induces cancer apoptosis [66]. and autophagy throughvia B-Raf/MAPK/ERK the suppression pathwayof PI3K/AKT [65]. signalling Moreover, cascade it induces in cervical apoptosis cancer and [66]. autophagy through the throughsuppression the suppression of PI3K/AKT of signalling PI3K/AKT cascade signalling in cervical cascade cancer in cervical [66]. cancer [66]. Diterpenes Diterpenes Diterpenes Oridonin Oridonin Oridonin

Oridonin is an organic heteropentacyclic compound isolated from the leaves of the medicinal Oridonin is an organic heteropentacyclic compound isolated from the leaves of the medicinal herb OridoninRabdosia is rubescens an organic . It hasheteropentacyclic a role as an compound antineoplastic isolated agent, from an the angiogenesis leaves of the inhibitor, medicinal an herb Rabdosia rubescens. It has a role as an antineoplastic agent, an angiogenesis inhibitor, an herbapoptosis RabdosiaRabdosia inducer, rubescens rubescens an .anti-asthmatic It. It has has a role a role as agent, an as antineoplastic an a plant antineoplastic metabolite agent, an agent, and angiogenesis an an antibacterial angiogenesis inhibitor, agent. inhibitor, an apoptosisOridonin an apoptosis inducer, an anti-asthmatic agent, a plant metabolite and an antibacterial agent. Oridonin apoptosisinducer,inhibits oral an inducer, anti-asthmatic cancer an growth anti-asthmatic agent, and aPI3K/Akt plant agent, metabolite signallinga plant andmetabolite pathway an antibacterial and [67]. an Moreover, antibacterial agent. Oridonin the agent. compound inhibits Oridonin oralhas inhibits oral cancer growth and PI3K/Akt signalling pathway [67]. Moreover, the compound has inhibitscancershown growthenhanced oral cancer and anticancer PI3K/Akt growth efficacyand signalling PI3K/Akt by pathwayinhibiting signalling [67 PI3K/AKT]. Moreover,pathway and [67]. the Ras/Raf/MEK/ERK compound Moreover, has the shown compoundpathways enhanced [68].has shown enhanced anticancer efficacy by inhibiting PI3K/AKT and Ras/Raf/MEK/ERK pathways [68]. shownanticancerOridonin enhanced upregulates efficacy anticancer by PTEN inhibiting efficacy through PI3K/AKT by activatinginhibiting and PI3K/AKT p38 Ras/Raf/MEK/ERK MAPK and and Ras/Raf/MEK/ERK inhibits pathways proliferation pathways [68]. in Oridonin human [68]. Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human Oridoninupregulatescolon cancer upregulates PTENcells [69]. through PTEN activating through p38 activating MAPK p38 and MAPK inhibits and proliferation inhibits proliferation in human colon in human cancer colon cancer cells [69]. coloncells [ 69cancer]. cells [69]. Neolignan biphenol Neolignan biphenol Neolignan biphenol

Honokiol is a lignan isolated from the bark, seed cones and leaves of trees belonging to the Honokiol is a lignan isolated from the bark, seed cones and leaves of trees belonging to the genusHonokiol Magnolia. is a lignan It suppresses isolated from proliferation the bark, and seed inducescones and apoptosis leaves of via trees regulation belonging ofto the genusHonokiol Magnolia. is a lignan It suppresses isolated from proliferation the bark, seed and cones induces and leaves apoptosis of trees via belonging regulation to the of genus the genusPTEN/PI3K/AKT Magnolia. pathway It suppresses in human proliferation osteosarcoma and cells induces [70]. Itapoptosis has also via been regulation shown to ofinduce the PTEN/PI3K/AKTMagnolia. It suppresses pathway proliferation in human and osteosarcoma induces apoptosis cells [70]. via regulationIt has also of been the PTEN/PI3K/AKT shown to induce PTEN/PI3K/AKTautophagy and apoptosis pathway in in osteosarcoma human osteosarcoma cells through cells PI3K/AKT/mTOR [70]. It has also signalling been shown pathway to induce [71]. autophagypathway in and human apoptosis osteosarcoma in osteosarcoma cells [70 cells]. Itthrough has also PI3K/AKT/mTOR been shown to signalling induce autophagy pathway [71]. and autophagyMoreover, itand has apoptosis been reported in osteosarcoma en effect on cells proliferation, through PI3K/AKT/mTORmigration and invasion signalling in nasopharyngeal pathway [71]. Moreover,apoptosis init has osteosarcoma been reported cells en througheffect on PI3K/AKT/mTORproliferation, migration signalling and invasion pathway in nasopharyngeal [71]. Moreover, Moreover,carcinoma itcells has [72]. been Taken reported everything en effect into on proliferation,consideration, migration honokiol and has invasionshown proapoptotic in nasopharyngeal effects carcinomait has been cells reported [72]. enTaken effect everything on proliferation, into consideration, migration and honokiol invasion has in shown nasopharyngeal proapoptotic carcinoma effects carcinomain melanoma, cells [72]. sarcoma, Taken myeloma,everything leukaemia,into consideration, bladder, honokiol lung, has prostate, shown oral proapoptotic squamous effects cell incells melanoma, [72]. Taken everything sarcoma, myeloma, into consideration, leukaemia, honokiol bladder, has shown lung, proapoptotic prostate, oral effects squamous in melanoma, cell incarcinomas, melanoma, in sarcoma, glioblastoma myeloma, multiforme leukaemia, cells and bladder, colon lung, cancer prostate, cell lines. oral Honokiol squamous inhibits cell carcinomas,sarcoma, myeloma, in glioblastoma leukaemia, bladder, multiforme lung, cells prostate, and oral colon squamous cancer cell cell carcinomas, lines. Honokiol in glioblastoma inhibits carcinomas,phosphorylation in glioblastomaof Akt, p44/42 multiforme mitogen-activated cells and protein colon kinase cancer (MAPK) cell lines. and Honokiol Src kinase. inhibits It also phosphorylationmultiforme cells of and Akt, colon p44/42 cancer mitogen-activated cell lines. Honokiol protein inhibits kinase phosphorylation(MAPK) and Src of kinase. Akt, p44/42It also phosphorylationacts on the PI3K/AKT/mTOR of Akt, p44/42 pathway mitogen-activated in tumour protein cells while kinase maintaining (MAPK) and pathway Src kinase. activity It inalso T actsmitogen-activated on the PI3K/AKT/mTOR protein kinase pathway (MAPK) in tumour and Src cells kinase. while It also maintaining acts on the pathway PI3K/AKT/mTOR activity in T actscells. on the PI3K/AKT/mTOR pathway in tumour cells while maintaining pathway activity in T cells.pathway in tumour cells while maintaining pathway activity in T cells. cells. Coumestans Coumestans Coumestans Wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan)(7-methoxy-5,11,12-trihydroxy-coumestan) Wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan) Wedelolactone (7-methoxy-5,11,12-trihydroxy-coumestan)

It is a plant-derived natural product synthesized mainly by members belonging to the It is is a a plant-derived plant-derived natural natural product product synthesized synthesized mainly mainly by members by members belonging belonging to the Asteraceae to the AsteraceaeIt is a family. plant-derived Wedelolactone natural inhibits product breast synthesized cancer-induced mainly osteoclastogenesis by members belonging by inhibiting to the Asteraceaefamily. Wedelolactone family. Wedelolactone inhibits breast inhibits cancer-induced breast cancer-induced osteoclastogenesis osteoclastogenesis by inhibiting by AKT/mTOR inhibiting AsteraceaeAKT/mTOR family. signalling Wedelolactone [73]. It also inhibits has been breast shown cancer-induced to induce caspase-dependentosteoclastogenesis by apoptosis inhibiting in AKT/mTORsignalling [73 signalling]. It also has [73]. been It shown also has to induce been shown caspase-dependent to induce caspase-dependent apoptosis in prostate apoptosis cancer cells in AKT/mTORprostate cancer signalling cells via [73].downregulation It also has of been PKCε shown and without to induce inhibition caspase-dependent of AKT kinase. apoptosis in prostatevia downregulation cancer cells ofvia PKC downregulationε and without of inhibition PKCε and of without AKT kinase. inhibition of AKT kinase. prostate cancer cells via downregulation of PKCε and without inhibition of AKT kinase.

Pharmaceuticals 2019, 12, 4 11 of 21 Pharmaceuticals 2019, 14, 4 11 of 21

AlkaloidsAlkaloids

CurcuminCurcumin fromfrom turmericturmeric

Curcumin (diferuloylmethane) the major ingredient of the popular Indian spice turmeric, Curcumin (diferuloylmethane) the major ingredient of the popular Indian spice turmeric, Curcuma Curcuma longa L., is a member of the ginger family. longa L., is a member of the ginger family. Curcumin, is a polyphenol with molecular targets for cancer control [74] and has a Curcumin, is a polyphenol with molecular targets for cancer control [74] and has a multifaceted multifaceted role in cancer prevention and treatment [75]. The following reviews focus on the role role in cancer prevention and treatment [75]. The following reviews focus on the role of curcumin in of curcumin in cancer and treatment with respect to the PI3K/AKT pathway [76] and its cancer and treatment with respect to the PI3K/AKT pathway [76] and its antiangiogenic activity in antiangiogenic activity in cancer therapy [77], respectively. cancer therapy [77], respectively. 7. Protein Kinase Inhibition by Natural Compounds. Is This An Option? 7. Protein Kinase Inhibition by Natural Compounds. Is This an Option? Polyketides are a heterogeneous group of secondary metabolites. We have focused in this Polyketides are a heterogeneous group of secondary metabolites. We have focused in this review review on the largest group of these compounds, which are the flavonoids with more than 9000 on the largest group of these compounds, which are the flavonoids with more than 9000 known known compounds today. There are other polyketides such as stilbenes and curcuminoids which compounds today. There are other polyketides such as stilbenes and curcuminoids which are less are less widely distributed, yet some compounds from these groups, e.g., resveratrol and curcumin widely distributed, yet some compounds from these groups, e.g., resveratrol and curcumin have have received much attention for their multiple effects on various diseases [78]. We also would like received much attention for their multiple effects on various diseases [78]. We also would like to to mention the terpenoids (isoprenoids), which are the largest class of natural products in plants mention the terpenoids (isoprenoids), which are the largest class of natural products in plants and and comprise more than 40,000 different structures. According to the number of isoprene molecules comprise more than 40,000 different structures. According to the number of isoprene molecules incorporated, they can be classified into hemiterpenes (C5), monoterpenes (C10), sesquiterpenes incorporated, they can be classified into hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), triterpenes (C30), etc. Table 1 shows representatives for sesquiterpenes and (C15), diterpenes (C20), triterpenes (C30), etc. Table1 shows representatives for sesquiterpenes and diterpenes. We have also included a neolignan biphenol compound, i.e., honokiol. Despite the large diterpenes. We have also included a neolignan biphenol compound, i.e., honokiol. Despite the large number of structures only a few compounds have been identified as protein kinase inhibitors. Since number of structures only a few compounds have been identified as protein kinase inhibitors. Since most of the serine/threonine kinase inhibitors known so far belong to the flavonoids our focus in most of the serine/threonine kinase inhibitors known so far belong to the flavonoids our focus in this this review is on these compounds. review is on these compounds. Potentially, flavonoids, which are ATP mimetic, can target all 500 protein kinases. We have Potentially, flavonoids, which are ATP mimetic, can target all 500 protein kinases. We have focused focused on a selection of serine/threonine protein kinases, which are part of the major signalling on a selection of serine/threonine protein kinases, which are part of the major signalling pathways as pathways as shown in Figure 1. The eleven kinases listed in Table 1 were identified in a linked shown in Figure1. The eleven kinases listed in Table1 were identified in a linked analysis in PubMed analysis in PubMed inserting the natural compounds listed in Table 1: ((natural compound) AND inserting the natural compounds listed in Table1: ((natural compound) AND protein kinase) AND protein kinase) AND cancer). Altogether 22 compounds from Table 1 were linked as described cancer). Altogether 22 compounds from Table1 were linked as described above. The numbers in above. The numbers in Table 1 associated to the individual compounds indicate the number of hits. Table1 associated to the individual compounds indicate the number of hits. In the case of apigenin 188 In the case of apigenin 188 publications were found when linked with the term protein kinase and publications were found when linked with the term protein kinase and cancer. The highest number cancer. The highest number under this linkage analysis that we found was 621 hits for curcumin. under this linkage analysis that we found was 621 hits for curcumin. This does not come as a surprise This does not come as a surprise since there is a plethora of research articles available on curcumin since there is a plethora of research articles available on curcumin spanning already several decades. spanning already several decades. The number of hits increases on a daily basis, especially for the The number of hits increases on a daily basis, especially for the most popular compounds listed in most popular compounds listed in row number one. We have foremost considered those kinases row number one. We have foremost considered those kinases that belong to the signal transduction that belong to the signal transduction pathways shown in Figure 1. pathways shown in Figure1. The results shown in Table 2 come as no surprise. All of the listed kinases show a large The results shown in Table2 come as no surprise. All of the listed kinases show a large agreement agreement with respect to the natural compounds involved in the linked search. Although this with respect to the natural compounds involved in the linked search. Although this approach may approach may look trivial it demonstrates that the assumption of a general interaction of the look trivial it demonstrates that the assumption of a general interaction of the kinases and natural kinases and natural compounds is as expected because of the binding to the ATP site. Although compounds is as expected because of the binding to the ATP site. Although 9000 flavonoids have been 9000 flavonoids have been so far identified, only a small selection has been investigated thoroughly so far identified, only a small selection has been investigated thoroughly with respect to protein kinase with respect to protein kinase interaction. Hence, we postulate that many more kinase will show interaction. Hence, we postulate that many more kinase will show similar interaction patterns with similar interaction patterns with natural compounds as seen in Table 2. natural compounds as seen in Table2.

Pharmaceuticals 2019, 12, 4 12 of 21

Table 1. Classification of flavonoids and other polyphenolic compounds.

Neolignan Flavones Flavonols Flavanones Flavanonols Isoflavones Flavan-3-ols/Catechins Anthocyanins Sesquiterpenes Diterpenes Coumestans Alkaloids Biphenols Apigenin Quercetin Naringenin Silibinin Genistein Epigallocatechin-3-gallate Delphinidin Parthenolide Oridonin Honokio Wedelolactone Curcumin 188 344 37 115 794 309 33 52 50 l39 14 621 Luteolin Kaemphero Hesperidin Silymarin Daidzein Cyanidin 116 l86 24 130 68 24 Baicalein Fisetin Hesperetin Taxifolin 67 47 18 6 The numbers indicate citations found for the compounds using a linked search: ((compound) AND protein kinases) AND cancer) in PubMed. Pharmaceuticals 2019, 12, 4 13 of 21

Table 2. Selection of serine/threonine-specific kinases (STKs) shown to be inhibited by natural compounds.

Protein Kinase Natural Compound Apigenin, Fisetin, Naringenin, Silibinin, Parthenolide, Oridonin, Honokiol, PI3K Genistein, EGCG, Taxifolin, Ellagic acid, Emodin, Curcumin Apigenin, Fisetin, Quercetin, Naringenin, Silibinin, Parthenolide, Oridonin, AKT Curcumin EGCG, Luteolin, Resveratrol, Genistein, Taxifolin, Wedelolactone, Ellagic acid, Emodin, Harmine, Curcumin Apigenin, Quercetin, Genistein, EGCG, Curcumin, Oridonin, Silibinin, mTOR Wedelolactone, Curcumin Apigenin, Curcumin, Berberine, Resveratrol, Curcumin, Luteolin, GSK3β Quercetin, Curcumin Apigenin, Coumestrol, Resorufin, Gallaflavin, Fisetin, Nortangeretin, CK2 Ellagic acid RAF Curcumin, EGCG, Resveratrol, Parthenolide Apigenin, Quercetin, Silibinin, Oridonin, Genistein, Parthenolide, Genistein, MEK/ERK1/2 Honokiol, Cyanidin, Berberine, Quercetin, Ellagic acid, Emodin PKC Apigenin, Wedelolactone, Curcumin CamKK Apigenin, Curcumin, Resveratrol, Berberine, EGCG (stimulation) IKK Apigenin, Wedelolactone JNK Apigenin, Quercetin, Silibinin, Cyanidin, Parthenolide, Hesperetin

8. How Can One Cope with the Adverse Effects of Various Compounds Targeting Driver Gene Products? The Role of Small Molecule Inhibitors A better understanding of signalling networks operating in cancer cells has helped to define the biology of malignant tumours and to demonstrate the importance of components of core signalling pathways that promote and sustain the tumour microenvironment. The observation that oncogenic mutations are responsible for the induction of molecular aberrations observed in cancer progression have boosted the development of small molecules inhibitors of oncogene products in order to target and weaken oncogenic signalling. Chemical compounds that target multiple critical protein kinases or specific ones (i.e., in the case of tumours that are highly dependent on a single genetic aberration) may turn out to be a clinical success, since the success rate for bringing cancer drugs to the market is very limited [6]. One of the major reasons is toxicity, which often can be observed in late stages of clinical development. A consideration pertinent to this is that the adverse effects that may derive from a particular compound can be considered as off-target toxicity. Driver protein kinase(s) play a crucial role in normal cells by controlling vital processes as cell growth and division, yet, when deregulated, they contribute to malignant transformation. Thus, inhibition of these kinases is a desirable option interfering with tumourigenesis. One could predict that the design of compounds able to specifically target aberrant protein kinase(s) and not their normal counterparts or to target protein kinases whose (over)expression is strictly required for cells undergoing the process of transformation would perhaps turn out to be a more effective strategy to treat cancer. In this respect, the survival of cancer cells depends on multiple factors which include not only the expression of oncogenic drivers but also proteins that do not per se cause cell transformation but are essential for tumour cell survival and possibly for coping with increased levels of various stressors. The concept of non-oncogene addiction [79] indeed reflects the notion that cancer cells heavily depend on this particular group of proteins whose expression is often found upregulated. Thus, the idea of harming their function and/or expression is considered an attractive treatment modality, as cancer cells would not tolerate these perturbations as easily as normal cells. We would like to focus on one protein kinase with respect to non-oncogene addiction. Pharmaceuticals 2019, 12, 4 14 of 21

Protein Kinase CK2 Within the super family of protein kinases, protein kinase CK2 represents a convincing example of non-oncogene addiction [80]. CK2 is a highly conserved serine/threonine kinase composed of two catalytic subunits (i.e., α and/or α’) and two regulatory β-subunits with the ability to participate in the regulation of a broad range of cellular processes from motility to cell division, survival and metabolism [81–83]. Compelling evidence has shown that CK2 is involved in various stages of cell transformation and cancer development. Abnormally high levels of this enzyme have been consistently reported in all investigated cancer cell types but also in samples isolated from cancer patients while somatic mutations have hardly been detected [84]. CK2 activity and expression levels are elevated in many cancers of diverse genetic background including breast [85], lung [86], prostate [87], colorectal [88], renal [89,90] and leukaemias [91]. A more direct link between CK2 and cell transformation has been demonstrated in transgenic mice. Co-expression of CK2α and c-Myc results in polyclonal neonatal leukaemia [92]. Similarly, expression of Tal-1 transcription factor in transgenic mice leads to accelerated lymphoid malignancy in the presence of the CK2α transgene [93]. Xu et al. [94] showed a direct correlation between overexpression of CK2 and accelerated onset of lymphomas in mice heterozygous and homozygous for the p53 null allele, respectively, confirming the contribution of CK2 to tumourigenesis. This overwhelming collection of data strongly supporting the role of CK2 in cancerogenesis, has, so far, failed to provide a complete picture of the molecular mechanisms regulated by CK2 in the context of cell transformation and cancer. Nevertheless, the fact that tumour cells unlike normal cells rely on elevated levels of CK2 for sustaining the high proliferation pace and survival supports the notion that inhibition of this protein kinase may represent a clever way to treat most common types of malignant tumour by severely damage cancer cells while leaving healthy tissue largely unaffected. CK2 orchestrates a broad network of cellular functions and even if its expression has a modest effect on cell transformation, the control exerted on individual components of intracellular signalling cascades may altogether have a considerable impact on malignant transformation. Numerous small molecules inhibitors of CK2 have been developed over the past 30 years displaying reduction in cancer cells viability and induction of cell death to a variable extent in tissue culture and animal models [95]. Two of the compounds most recently identified through high throughput screenings of natural compound libraries comprise 4-[(E)-(fluoren-9- ylidenehydrazinylidene)- methyl]benzoic acid (E9 [96,97]) and 1,3-Dichloro-6-[(E)-((4-methoxyphenyl) imino)methyl] diben- zo(b,d) furan-2,7-diol (D11 [98–100]). In particular, E9 was tested in vivo in murine xenograft models exhibiting significant antitumour effects without showing detrimental effects on mouse body weight and organ toxicity [97]. Overall, data obtained in vivo employing inhibitors of CK2, although preliminary, unequivocally demonstrate that inhibition of this enzyme results in anti-neoplastic effects in various types of cancer without causing life-threatening side effects providing evidence of a possible clinical benefit.

9. Future Perspectives, Challenges and Limitations Natural products are now considered as an alternative for synthetic drugs. These natural products are present in numerous sources like, plants, microorganisms, fungi, etc. Besides being non-toxic in nature they are considered less expensive. There are trends to show that the mainstream in pharmacological research is moving away from single molecule or single target approach to combinations and multiple target approaches [23]. In 2013, the FDA approved 1453 new chemical entities from which 40% comprised of natural products or analogues of natural compounds [101,102]. Natural products alone or in combination have been able to induce apoptosis as well as chemosensitised those cell lines that were resistant to conventional drugs. A key obstacle in the development of a specific inhibitor is the variation in efficacy observed in the cell line based experiments and rodent models during drug discovery phase leading to the final efficacy in patients [6]. Since the development of the first kinase inhibitor in the early 1980s, over 40 kinase inhibitors have received FDA approval for treatment of malignancies such a breast and lung cancer. Moreover, about 150 kinase-targeted Pharmaceuticals 2019, 12, 4 15 of 21 drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development [6]. Kinase inhibitors symbolize a class of targeted cancer therapeutic agents with limited non-specific toxicities. Based on the latest update published in November 2018, forty-nine inhibitors with activity targeted to one or multiple kinases have been approved by FDA for clinical use of which the majority are directed against tyrosine kinases (http://www.brimr.org/PKI/PKIs.htm[6]). Only a few inhibitors directed against serine/threonine kinases, e.g., B-Raf are in clinical use [6]. Serine/threonine kinase inhibitors targeting mTOR, MAPK Aurora kinases and CK2 are under development for clinical application [103,104]. We have focused on the classical major signal transduction pathways shown in Figure1. The focus is on natural compounds derived from plants, especially on flavonoids. Yet, it should not go unmentioned that many other protein kinases are in the limelight of current research in academia and in pharmaceutical companies. This concerns protein kinase B, polo-like kinase I, cyclin-dependent kinases and others. CDKs also have been targeted with natural compounds from other sources than plants, e.g., from marine organisms. This is a potential new source for finding further potent kinase inhibitors [105–107]. Plants are subject to many “attacks” by viruses, bacteria and fungi. Therefore, it was mandatory for plants to develop mechanisms of defence through so-called secondary metabolites, which usually are not as vital as primary metabolites such as carbohydrates and amino acids. An example of secondary metabolites are alkaloids, primarily composed of nitrogen, that are widely used in medicine. With currently more than 12,000 known structures, alkaloids represent one of the biggest groups of natural compounds. An exhaustive overview over the different classes of natural products is described in Springob et al., [108]. Most of the protein kinase inhibitors isolated from plants are flavonoids, which are part of the polyketides. But there are also other members of this chemical group such as the anthrones and anthraquinones with representatives such as emodin and hypericin. Both compounds have been shown to inhibit protein kinases such as protein tyrosine kinase p65lck and CK2 [109,110]. As with the alkaloids most of the members of the flavonoid group existed as valuable “folk medicine” beneficial for many other diseases than cancer. But even when shown to be useful for treating cancer, other mechanisms than interference with protein kinases have been described. Wine polyphenol extracts have been shown to arrest cell cycle, induce apoptosis through caspase activation, and induce changes in metalloproteinase (MMP) activities. Resveratrol, a stilbene found in many food sources and in red wine grapes is assumed to have multiple benefits on human health. It has been shown to inhibit protein kinases such as AKT, RAF, MEK/ERK1/2, CamKK and JNK (Table2). Therefore it is tempting to speculate that it is the interference with the various protein kinases, which is responsible for the observed “anticancer effects”. Yet, this may be more apparent than real given the low amounts of resveratrol taken up by consumption of wine. Even the intake of the pure resveratrol compound would not be sufficient to have a measurable effect on cellular protein kinase activity. Moreover, given the fairly large number of different protein kinases that are affected by resveratrol, one cannot exclude negative side effects when large amounts are employed. The same argument applies to other natural compounds that have been described throughout this review. At the moment there are too many different biological aspects known which are tempting to assume that they are responsible for the observed health effects. Each compound for itself is not efficient enough in plant extracts to account for a successful treatment of cancer. There are increasing reports of the isolation of protein kinase inhibitors from other sources, beside plants. Recently protein kinase inhibitors have been isolated from marine sources [106,107]. This is a new and promising approach in the search for new types of kinase inhibitors. However, since there are so many other factors: environmental, genetic and personal habits of nutrition, physical exercise, etc.; food-related arguments alone are not enough. The search for the ‘magic bullet’, where a particular molecule is targeted may give way for a broader application of flavonoids, simply through the fact, that they intervene on many cellular Pharmaceuticals 2019, 12, 4 16 of 21

‘battle fields’. Perhaps this fact will lead in the future to a successful anticancer therapy when applied correspondingly.

Funding: This work was supported with funding from the Novo Nordisk Foundation (Grant NNF17OC0028720) to B.G. Conflicts of Interest: The authors declare that they do not have conflicts of interest with the content of this article.

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