Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells

doi:10.1016/0167-4889(94)90299-2

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Volume 1224, Issue 3, 30 December 1994, Pages 597-600

https://doi.org/10.1016/0167-4889(94)90299-2 Get rights and content

Abstract

We explored the mechanism of antigrowth action of Curcumin by investigating its effect on epidermal growth factor (EGF) receptor intrinsic kinase activity in the human epidermoid carcinoma A431 cells. The short-term treatment of cells with Curcumin inhibited EGF receptor intrinsic kinase activity up to 90% in a dose- and time-dependent manner, and also inhibited EGF-induced tyrosine phosphorylation of EGF receptors. The observed early effects of Curcumin were mediated via a cellular mechanism(s), and preceded the period when inhibition of cell growth occurred.

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Breast cancer is the most frequently diagnosed malignancy in women in the western world. Oxidative stress is one of the important pathogenic factors of cancer development. Among the antioxidants, curcumin (1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione; diferuloylmethane) is a dietary natural yellow pigment derived from the rhizome of the herb Curcuma longa (Zingiberaceae). This study evaluated the effects of curcumin on oxidative stress in an established in vitro experimental breast cancer model (Alpha-model) as well as in isolated cells derived from breast specimens. Such model was developed with the immortalized breast cell line, MCF-10F, that was exposed to low doses of high linear energy transfer (LET) α particles (150 keV/μm) of radiation, values comparable to α particles emitted by radon progeny, and cultured in the presence of 17β-estradiol. It consisted of cell lines in different stages of transformation: (i) MCF-10F, (ii) an estrogen-treated, called Estrogen, (iii) a malignant one, called Alpha3, (iv) a malignant and tumorigenic one, called Alpha5, and (v) a tumor cell line, called Tumor2 derived from a tumor after injection of previous one in nude mice. Free radical production is ubiquitous in all organisms and it is enhanced in many diseases. Curcumin interferes with multiple genes that promote carcinogenesis, thereby affecting genomic instability. Alteration in protein expressions involved in key signaling pathways and epithelial-mesenchymal transition render this model an important tool for monitoring effects of natural dietary compounds in breast carcinogenesis.
Curcumin as tyrosine kinase inhibitor in cancer treatment
2019, European Journal of Medicinal Chemistry
Citation Excerpt :
Placement of the curcumin particle in the cell membrane increases membrane viscosity what in turn causes receptor lateral mobility decrease, and thus receptor dimerisation rate and modulation of autophosphorylation [84]. Curcumin reduces EGFR expression and EGFR mRNA levels in bladder cancer [85], reduces EGFR phosphorylation of oral squamous cell carcinoma [86], inhibits EGFR kinase activity in the epidermoid carcinoma cells [87] and in colon cancer cells [88]. Experimental studies have also confirmed the positive effect of curcumin on the non-small cell lung cancer (NSCLC).
Curcumin is a natural substance known for ages, exhibiting a multidirectional effect in cancer prevention and adjuvant cancer therapies. The great advantage of using nutraceuticals of vegetable origin in comparison to popular cytostatic drugs is the minimized side effect and reduced toxicity. The targets in oncological therapy are, among others, tyrosine kinases, important mediators of signaling pathways whose impaired expression is observed in many types of cancer. Unfortunately, the hydrophobic nature of the curcumin molecule often limits its bioavailability, which is why many studies focus on the chemical modification of this compound. Current research is aimed at modifying structures that improve the pharmacokinetic parameters of curcumin, e.g. the formation of nanoparticles, complexes with metals or the synthesis of curcumin derivatives with functional substituents that allow tumor targeting. The article is a review and analysis of current literature on the properties of curcumin and its derivatives in the treatment of cancers directed to signaling pathways of tyrosine kinases and confronts the problem of low assimilation of curcumin with potential therapeutic effects.
EGFR inhibition by curcumin in cancer cells: A dual mode of action
2015, Biomacromolecules
Epidermal Growth Factor Receptor (EGFR) is an important target of anticancer therapy. Nowadays, the search for new molecules inhibiting this receptor is turning toward natural substances. One of the most promising natural compounds that have shown an anti-EGFR activity is curcumin, a polyphenol found in turmeric. Its effect on the receptor kinase activity and on the receptor autophosphorylation has been already described, but the mechanism of how curcumin interacts with EGFR is not fully elucidated. We demonstrate that the mode of action of curcumin is dual. This polyphenol is able to inhibit directly but partially the enzymatic activity of the EGFR intracellular domain. The present work shows that curcumin also influences the cell membrane environment of EGFR. Using biomimetic membrane models, we show that curcumin insertion into the lipid bilayer leads to its rigidification. Single particle tracking analyses performed in the membrane of A431 cancer cells confirmed that this effect of curcumin on the membrane slows down the receptor diffusion. This is likely to affect the receptor dimerization and, in turn, its activation.
Ensemble docking and molecular dynamics identify knoevenagel curcumin derivatives with potent anti-EGFR activity
2014, Gene
Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is an attractive target for cancer therapy. Despite a number of effective EGFR inhibitors that are constantly expanding and different methods being employed to obtain novel compounds, the search for newer EGFR inhibitors is still a major scientific challenge. In the present study, a molecular docking and molecular dynamics investigation has been carried out with an ensemble of EGFR-TK structures against a synthetically feasible library of curcumin analogs to discover potent EGFR inhibitors. To resolve protein flexibility issue we have utilized 5 EGFR wild type crystal structures during docking as this gives improved possibility of identifying an active compound as compared to using a single crystal structure. We then identified five curcumin analogs representing different scaffolds that can serve as lead molecules. Finally, the 5 ns molecular dynamics simulation shows that knoevenagel condensate of curcumin specifically C29 and C30 can be used as starting blocks for developing effective leads capable of inhibiting EGFR.
Curcumin, Oxidative Stress, and Breast Cancer
2014, Cancer: Oxidative Stress and Dietary Antioxidants
Breast cancer is the most frequent malignancy diagnosed in women in the western world. Oxidative stress is one of the important pathogenic factors of cancer development. Among the antioxidants, curcumin (1, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione; diferuloylmethane) is a dietary natural yellow pigment derived from the rhizome of the herb Curcuma longa (Zingiberaceae). This chapter evaluates the oxidative effect of curcumin in an established in vitro experimental breast cancer model (Alpha model) as well as in isolated cells derived from breast specimens. Such a model was developed with the immortalized breast cell line, MCF-10F, which was exposed to low doses of high linear energy transfer (LET) α particles (150 keV/μm) of radiation, values comparable to α particles emitted by radon progeny, and cultured in presence of 17β-estradiol. It consisted of cell lines in different stages of transformation: (1) MCF-10F; (2) an estrogen-treated, named Estrogen; (3) a malignant one, named Alpha3; (4) a malignant and tumorigenic one, named Alpha5; and (5) a tumor cell line, named Tumor2, derived from a tumor after injection of previous one in nude mice. Free radical production is ubiquitous in all organisms and it is enhanced in many diseases. Curcumin interferes with multiple genes that promote carcinogenesis, therefore affecting genomic instability. Alteration of protein expressions involved in key signaling pathways render this model an important tool for monitoring effects of natural dietary compounds in breast carcinogenesis.
Differential anti-tumor activities of curcumin against Ras- and Src-activated human adenocarcinoma cells
2013, Biochemical and Biophysical Research Communications
Citation Excerpt :
Specifically, the epidermal growth factor receptor (EGFR) tyrosine kinase has been reported as a potential target of curcumin [12,13]. Curcumin inhibits the EGFR intrinsic kinase activity in human epidermoid [13], breast [14], prostate [15,16], and colon cancer [17]. Curcumin has been shown to block EGFR signaling by preventing EGFR tyrosine phosphorylation and suppressing EGFR gene expression [18].
Although curcumin has been studied as a potential anticancer drug targeting multiple signaling molecules, the role of oncogenic Src and Ras in curcumin sensitivity remains unknown. Using HAG-1 human adenocarcinoma cells transfected with either activated Src or Ras, we investigated here the functional role of these oncogenes in curcumin sensitivity. Activation of either Src or Ras did not confer resistance to curcumin, compared to vehicle-transfected cells. Curcumin enhanced Erk1/2 predominantly in Ras-activated cells, but inhibited Akt and its downstream molecules (mTOR and S6K1) regardless of these oncogene activations. The sub-G0/G1 apoptotic populations were substantially increased with demonstrable cleavage of PARP, but this increase was most prominent in Src-activated cells. Suppression of Bcl-xL level and enhanced expression of Bax were demonstrated in Src-activated, but not Ras-activated cells. By contrast, drastic increases of G₂/M cell populations were seen in Ras-activated cells rather than Src-activated cells, suggesting a potential role of Ras/Erk1/2 activation in curcumin-induced G₂/M arrest. These data indicate that curcumin-induced growth inhibition would be mediated mainly by G₂/M arrest in Ras-driven cells but by apoptosis induction in Src-driven cells, providing a mechanistic rationale for the potential use of curcumin in the treatment of human cancers with activated Src or Ras.

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Rapid reportInhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells

Abstract

Cancer Lett.

J. Biol. Chem.

J. Biol. Chem.

Cell

Science

J. Pharm. Pharmacol.

Nutr. Cancer

Cancer Res.

Carcinogenesis

Eur. J. Pharm.

Carcinogenesis

Carcinogenesis

Rapid report
Inhibitory effect of curcumin on epidermal growth factor receptor kinase activity in A431 cells