Inhibition of epidermal growth factor receptor over-expressing cancer cells by the aphorphine-type isoquinoline alkaloid, dicentrine

Abstract

To cite this version:V. Badireenath Konkimalla, Thomas Efferth. Inhibition of epidermal growth factor receptor overexpressing cancer cells by the aphorphine-type isoquinoline alkaloid, dicentrine. Biochemical Pharmacology, Elsevier, 2010, 79 (8) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 23A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2 AbstractThe extraordinary relevance of EGFR in tumour biology makes it an exquisite molecular target for tumor therapy. Despite considerable success with these EGFR tyrosine kinase inhibitors in cancer therapy, resistance against these chemical compounds develops owing to the selection of point-mutated variants of EGFR. Therefore, there is an urgent need for the identification of novel EGFR tyrosine kinase inhibitors for treating tumours caused by such EGFR mutants. We found a preferential cytotoxicity of dicentrine towards U87MG.EGFR transduced with a constitutively deletion-activated EGFR expression vector as compared to non-transduced wild-type U87MG cells. As determined by microarray-based mRNA expression profiling, this preferential cytotoxicity was accompanied with an activation of BRCA1-mediated DNA damage response, p53 signalling, G1/S and G2/M cell cycle regulation, and aryl hydrocarbon receptor pathways. The activation of these signalling routes might be explained by the fact that dicentrine intercalates DNA and induces DNA strand break by inhibition of DNA topoisomerases. The cell cycle might be arrested by dicentrineinduced DNA lesions.

Plant Derived Aporphinic Alkaloid S-(+)-Dicentrine Induces Antinociceptive Effect in Both Acute and Chronic Inflammatory Pain Models: Evidence for a Role of TRPA1 Channels

“…Among its biological properties, it has been reported a vasodilator and antihypertensive action [20], [21], [22], platelet aggregation inhibition [23], [24] and even a cytostatic effect against some tumor cell lines from mice and humans [25], [26], [27], [28]. Recently, our research group reported that S-(+)-dicentrine has an important antinociceptive effect in a model of visceral pain in mice [29], which lead us to further investigate its effect on inflammatory models of pain, as well as possible mechanisms of action.…”

Induction of Apoptosis by 3-Amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline via Modulation of MAPKs (p38 and c-Jun N-terminal Kinase) and c-Myc in HL-60 Human Leukemia Cells

“…Effects are also mediated that are relevant for the prevention or treatment of cancer. Berberine, 2,3 sanguinarine, 4 dicentrine, 5 and tetrandrine 6 induce cell cycle arrest or programmed cell death (apoptosis) via modulation of cancer-related biomarkers such as COX-2, PGE 2 receptor, p38 mitogen-activated protein kinase (p38 MAPK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and EGFR. Nitidine, sharing the isoquinoline backbone structure with indenoisoquinolines, has been reported to inhibit topoisomerase 1 (top1).…”

DNA topoisomerase‐directed anticancerous alkaloids: ADMET‐based screening, molecular docking, and dynamics simulation

“…Similarly, the alkaloid eleutherin has been reported to inhibit Topo II by inducing religation and dissociation of the enzyme from DNA . Moreover, alkaloids dicentrine (both Topo I and II) and lunacridine (Topo II only) have been reported to inhibit respective topoisomerases by intercalating the DNA helix .…”