Effect of an EGF-R selective tyrosine kinase inhibitor and an anti-androgen on LNCaP cells: Identification of divergent growth regulatory pathways

Jones, Helen E., Barrow, Denise, Dutkowski, Carol, Goddard, Lindy, Smith, Christopher, Harper, Maureen E. and Nicholson, Robert Ian 2001. Effect of an EGF-R selective tyrosine kinase inhibitor and an anti-androgen on LNCaP cells: Identification of divergent growth regulatory pathways. The Prostate 49 (1) , pp. 38-47. 10.1002/pros.1116

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Abstract

BACKGROUND The effect of an EGF-R selective tyrosine kinase (EGF-RTK) quinazoline inhibitor ZM252868 was determined on the androgen-sensitive human prostatic tumour cell line LNCaP, which can also respond via the EGF-R-regulated growth pathway for cell proliferation. Potential interaction or ‘cross-talk’ between steroid and the growth factor mitogen-activated protein kinase (MAPK) signalling pathway was also investigated. METHODS The responses of LNCaP cells to various growth factors in the absence and presence of the EGF-RTK inhibitor and/or steroid and anti-androgen Casodex, was determined using cell population analysis. The effect of the inhibitor on the expression of androgen receptor, EGF-R and activated MAPK was assessed immunocytochemically and changes in the MAPK signalling cascade were also determined using Western blotting techniques. RESULTS The ZM252868 inhibitor had no effect on LNCaP basal growth. At 100 nM and 1 μM concentrations, the inhibitor reduced the marked EGF- and TGF-α-stimulated LNCaP cell growth by 60% and to basal levels, respectively. Both bFGF- and 5α-DHT-stimulated growth were unaffected in this concentration range. The inhibitor (1 μM) decreased the expression of immunoreactive EGF-R but had no effect on androgen receptor levels. Activation of MAPK by EGF was noted, being down-regulated by the inhibitor at a concentration of 1 μM. MAPK was not activated by 5α-DHT. The anti-androgen Casodex reduced 5α-DHT-stimulated cell growth but had no effect on EGF-R mediated LNCaP growth or EGF-stimulated activated MAPK activity. Treatment with EGF and 5α-DHT in combination produced an additive effect on cell proliferation, with the anti-androgen and the EGF-RTK inhibitor only reducing the 5α-DHT- or EGF-stimulated portion of growth, respectively. CONCLUSIONS The study demonstrated the efficacy and selectivity of the ZM252868 inhibitor in inhibiting EGF-R mediated LNCaP cell growth. Additionally, no interaction between androgen and EGF-R mediated growth pathways was determined. Prostate 49:38–47, 2001

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	prostate cancer;tyrosine kinase;EGF-R
Publisher:	Wiley-Blackwell
ISSN:	0270-4137
Last Modified:	28 Jun 2019 03:01
URI:	https://orca.cardiff.ac.uk/id/eprint/70259

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