Targeting epidermal growth factor receptors

REVIEWTargeting epidermal growth factor receptors and downstream signaling pathways in cancer by phytochemicalsOnat Kadioglu&Jingming Cao&Mohamed E.M.Saeed&Henry Johannes Greten&Thomas EfferthReceived:23August2014/Accepted:25September2014#Springer International Publishing Switzerland2014Abstract Epidermal growth factor receptors(EGFR,HER2, HER3)activate signal transduction pathways involved in cancer proliferation,apoptosis,differentiation,metastasis, and angiogenesis.Their overexpression and activation are associated with unfavorable prognosis of cancer patients. Therefore,they are attractive targets for cancer therapy.Due to the development of drug resistance,therapeutic monoclonal antibodies and synthetic small molecule tyrosine kinase in-hibitors directed against EGFR family members may fail with fatal consequences for cancer patients.Medicinal plants raised considerable interest during the past years as valuable re-sources to develop novel treatment therapies targeting epider-mal growth factor receptors and their downstream signal transduction pathways.The present review gives an overview of isolated phytochemicals that inhibit these signaling routes. Inhibitors have been described that down-regulate the mRNA or protein expression of EGFR,HER2,or HER3or inhibit the phosphorylation of these receptors and/or their downstream signaling kinases.Remarkably,a wealth of in vivo experi-ments complemented in vitro data,indicating that natural products are also active in living animals bringing this re-search concept closer to clinical applicability.The combination of receptor-inhibiting natural product with stan-dard anticancer drugs frequently caused increased or even synergistic tumor inhibition in vitro and in vivo.It deserves further evaluation,if and how epidermal growth factor receptor-targeting natural products can be integrated into clin-ical oncology as well as to define their role for more tumor-specific and individualized tumor therapies.Keywords Drug resistance.Kinase.Molecular docking. Natural products.Signal transductionAbbreviationsART ArtesunateCET CephalotaxineEGFR Epidermal growth factor receptorGBM Glioblastoma multiformeHER Human epidermal growth factor receptorHHT HomoharringtonineNSCLC Non-small cell lung carcinomaSCLC Small cell lung carcinomaIntroductionChemotherapy regimens derived from results of clinical trials are valuable for determining optimal treatment options for large populations of patients.However,an individual patient’s response to chemotherapy can be very different from the predicted response of the average population,and the reasons for this variation are largely unknown.Several clinical and pathological factors have been identified as having prognostic value of treatment outcome and survival of cancer patients, e.g.,tumor size,lymph node and distant metastasis,tumor grade,and,more recently,specific molecular biomarkers. These prognostic factors help to classify the standard riskof O.Kadioglu:J.Cao:M.E.M.Saeed:T.EfferthDepartment of Pharmaceutical Biology,Institute of Pharmacy andBiochemistry,Johannes Gutenberg University,Mainz,GermanyH.J.GretenAbel Salazar Biomedical Sciences Institute,University of Porto,Porto,PortugalH.J.GretenHeidelberg School of Chinese Medicine,Heidelberg,GermanyT.Efferth(*)Institute of Pharmacy and Biochemistry,Johannes GutenbergUniversity,Mainz,Staudinger Weg5,55128Mainz,Germanye-mail:efferth@uni-mainz.deTarg OncolDOI10.1007/s11523-014-0339-4subpopulations of patients with the same tumor entity,but are still unable to predict the response of specific individuals to therapy.Therefore,there is an urgent need for reliable molec-ular tests to predict the individual patient’s risk of death from the disease irrespective of the treatment(prognostic markers) and sensitivity or resistance to chemotherapy(predictive markers).Such tests are necessary to develop individualized treatment schedules in the future.The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy towards targeted therapy with the aim to erad-icate tumor cells more efficiently with fewer side effects on normal tissue.Proteins encoded by genes carrying tumor-specific mutations serve as preferential targets for the devel-opment of novel drugs in cancer therapy.It is now well accepted that mutations in three main types of genes contribute to carcinogenesis:oncogenes,tumor suppres-sor genes,and stability genes.Oncogene activation(gain-of-function mutation)results from point mutations,chromosomal translocation,or gene amplification.Without such mutations, tumors cannot grow(tumor addiction).On the other hand, mutations in tumor suppressor genes are loss-of-function mu-tations,e.g.,missense mutations,chromosomal deletions or insertions,or epigenetic silencing,that allow the tumor to grow unchecked by normal cellular control mechanisms.Stability genes or caretakers including DNA repair genes controlling genomic stability and genes responsible for organizing mitotic recombination and chromosomal segregation.Inactivating mu-tations in these genes are dangerous because they increase the mutational rate in other genes.Out of the large number of potential targets for targeted chemotherapy,we focus on the epidermal growth factor receptor family in the present over-view.Growth factor receptors have a tremendous relevance in cancer biology.Therefore,the therapeutic intervention to si-lence the function of epidermal growth factors and their related signaling pathways represents a highly attractive approach to improve treatment success of solid tumors.Epidermal growth factor receptors in cancer biology There are four human epidermal growth factor receptors (EGFR/ERBB1/HER1,HER2/ERBB2/c-neu,HER3,and HER4).After ligand binding,they activate downstream sig-naling routes,which regulate proliferation,differentiation, apoptosis,metastasis,and angiogenesis.Their3D structures are represented in Fig.1.EGFR and HER2are over-expressed in many solid tumors,which is associated with unresponsive-ness to chemo-and radiotherapy as well as short survival times of patients(see below)[1].The heterodimer structure of EGFR/HER2is depicted in Fig.2.Thus far,10ligands have been identified,i.e.,the epidermal growth factor family (EGF,transforming growth factor-α,β-cellulin,epiregulin, HB-EGF,AR)and the neuregulin family(heregulin,neuregulins)[2,3].Upon binding of a ligand to an EGFR monomer,homo-dimerization takes place with a second EGFR molecule or with another HER member.Similarly, HER2can dimerize with HER3or HER4and HER3with HER4.Ligand binding and dimerization leads to intracellular phosphorylation of HER receptors and thereby activation of the downstream signaling pathways.The existence of10 ligands of different homo-and heterodimers consisting of four receptors create a considerable flexibility and complexity for signal transduction[2–4].This complexity is even further increased by varying the duration and strength of receptor signaling,receptor internalization,and recycling as well as rates of phosphorylation and dephosphorylation[5].Dimerization stimulates intrinsic tyrosine kinase activity of EGFR,which regulates specific signal transduction cascades, e.g.,Raf/Mek/Erk,PI3K/PDK1/Akt,PLCγ/PKC,MAPK, and JNK signaling routes.Constitutive EGFR activation as consequence of point mutations or gene amplification causes deregulated cellular processes such as proliferation,invasion, angiogenesis,cell motility,cell adhesion,inhibition of apo-ptosis,and DNA synthesis.The kinase activity is also associ-ated with autophosphorylation of five tyrosine residues in the C-terminal EGFR domain.Mutations affecting EGFR expres-sion foster carcinogenesis.The extraordinary relevance of EGFR in tumor biology makes it an exquisite molecular target for tumor therapy.Apart from therapeutic antibodies,several small molecules have been developed as EGFR inhibitors[6].For example,gefitinib (Iressa®;Astra Zeneca,DE,USA)and erlotinib(Tarceva®; OSI-774,Genentech Inc.,CA,USA)are first-generation in-hibitors used for the treatment of non-small cell lung cancer and other tumor types[7].Both quinazolinamines exhibit their inhibitory activity by competing with ATP for the ATP bind-ing pocket of EGFR.Despite considerable successes with these EGFR tyrosine ki-nase inhibitors in cancer therapy,resistance against these chemical compounds develop due to the selection of point-mutated EGFR variants[8].Therefore,there is an urgent need for the identification of novel EGFR tyrosine kinase inhibitors.In recent years,medic-inal plants came into the center of interest as resources for novel treatment strategies to target EGFR family members.Role of epidermal growth factor receptors for drug resistance and patient prognosisEGFR-expressing cell linesThe connection between EGFR and classical cytotoxic drug resistance has been known for more than two decades.Murine sarcoma180(S180)cells selected for resistance towards doxorubicin overexpress EGFR compared to drug-sensitive wild-type S180cells[9,10].As subsequently shown,EGFRTarg Oncolexpression also plays a role for drug resistance of tumor cells not previously selected treated with cytostatic drugs.Since kidney carcinomas are frequently unresponsive to chemother-apy,they represent a suitable model to study inherent drug resistance.EGFR expression of human primary cell cultures of renal cell carcinomas of 18patients subjected to hierarchi-cal cluster analyses showed that the expression of c-ErbB1and c-ErbB2was higher in resistant cell cultures compared to sensitive cell cultures [11].EGFR is involved in drug resistance by affection of apoptosis,DNA repair,or the induc-tion of resistance gene expression [12].These in vitro results were translated to clinical tumors.Tumors with EGFR expres-sion were significantly more frequent resistant to doxorubicin than EGFR negative or weakly expressing cancers [13,14].Glioblastoma multiforme (GBM)is the most aggressive form of adult human brain tumor [15].Malignant gliomas often show resistance to adjuvant radio-and chemotherapy due to the accumulation of genetic alterations that causeoncogeneFig.13D structure of human HER1/EGFR,HER2,HER3,and HER4.Extracellular and cytoplasmic domains of the proteins were retrieved from protein data bank (PDB)database and combined structures were formed with PyMolsoftwareFig.2Heterodimer of human HER1/HER2.Extracellular and cytoplasmic domains of the proteins were retrieved from PDB database and combined structures were formed with PyMol softwareTarg OncolT a b l e 1P h y t o c h e m i c a l s w i t h a c t i v i t y a g a i n s t E G F RC o m p o u n d P l a n tT u m o r t y p eE f f e c t R e f e r e n c eI c a r i s i d e I I (m e t a b o l i t e o f i c a r i i n )H e r b a e p i m e d i iA 431l u n g c a n c e rI n h i b i t i o n o f S T A T 3a n d M A P K /E 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