<i>In vitro</i> and <i>in silico</i> evaluation of EGFR targeting activities of curcumin and its derivatives

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Abstract

Curcumin and its derivatives are potential tyrosine kinase inhibitors that target EGFR.

Abstract

As polyphenols from Curcuma longa, curcumin and its derivatives possess numerous bioactivities. Herein, the epidermal growth factor receptor (EGFR) targeting activities of curcumin and its derivatives, as well as their structure–activity relationship were investigated. All of the tested compounds exhibited significant inhibition activities against EGFR kinase in homogeneous time-resolved fluorescence assay. Then their antiproliferative activities against Caco-2 were confirmed. The expressions of EGFR and phospho-EGFR proteins were regulated by curcumin and its derivatives. The 3,5-dione and methoxyl groups exerted significant influence on their electrostatic interactions with EGFR. Both hydrogen bonds and hydrophobic contacts were crucial for their binding with EGFR. Interestingly, their EGFR targeting activities were structure-dependent. The binding stabilities of curcumin and its derivatives were different from each other due to their structural diversity. This work indicated that curcumin and its derivatives were potential tyrosine kinase inhibitors that target EGFR.

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Jennifer L Stamos, Mark Sliwkowski, Charles Eigenbrot (2002)

The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-A resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.

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Roi Avraham, Yosef Yarden (2011)

Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks - such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer.

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Nicola Normanno, Antonella De Luca, Caterina Bianco … (2006)

The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTK). These trans-membrane proteins are activated following binding with peptide growth factors of the EGF-family of proteins. Evidence suggests that the EGFR is involved in the pathogenesis and progression of different carcinoma types. The EGFR and EGF-like peptides are often over-expressed in human carcinomas, and in vivo and in vitro studies have shown that these proteins are able to induce cell transformation. Amplification of the EGFR gene and mutations of the EGFR tyrosine kinase domain have been recently demonstrated to occur in carcinoma patients. Interestingly, both these genetic alterations of the EGFR are correlated with high probability to respond to anti-EGFR agents. However, ErbB proteins and their ligands form a complex system in which the interactions occurring between receptors and ligands affect the type and the duration of the intracellular signals that derive from receptor activation. In fact, proteins of the ErbB family form either homo- or hetero-dimers following ligand binding, each dimer showing different affinity for ligands and different signaling properties. In this regard, evidence suggests that cooperation of multiple ErbB receptors and cognate ligands is necessary to induce cell transformation. In particular, the growth and the survival of carcinoma cells appear to be sustained by a network of receptors/ligands of the ErbB family. This phenomenon is also important for therapeutic approaches, since the response to anti-EGFR agents might depend on the total level of expression of ErbB receptors and ligands in tumor cells.