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Titolo:
Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells
Autore:
Sharma, Y; Agarwal, C; Singh, AK; Agarwal, R;
Indirizzi:
Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci,Canc Ctr, Denver, CO 80262 USA Univ Colorado Denver CO USA 80262 ceut Sci,Canc Ctr, Denver, CO 80262 USA AMC Canc Res Ctr, Ctr Canc Causat & Prevent, Denver, CO USA AMC Canc Res Ctr Denver CO USA Ctr Canc Causat & Prevent, Denver, CO USA Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA Univ Pittsburgh Pittsburgh PA USA ell Biol & Physiol, Pittsburgh, PA USA
Titolo Testata:
MOLECULAR CARCINOGENESIS
fascicolo: 4, volume: 30, anno: 2001,
pagine: 224 - 236
SICI:
0899-1987(200104)30:4<224:IEOSOL>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
FLAVONOID ANTIOXIDANT SILYMARIN; SENCAR MOUSE SKIN; FACTOR RECEPTOR; CANCER PREVENTION; INTRAEPITHELIAL NEOPLASIA; PHOSPHATIDYLINOSITOL 3'-KINASE; ACTIVE CONSTITUENT; AUTONOMOUS GROWTH; KINASE INHIBITORS; TUMOR PROMOTION;
Keywords:
silymarin; silibinin; erbB1; prostate cancer; receptor signaling;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
71
Recensione:
Indirizzi per estratti:
Indirizzo: Agarwal, R Univ Colorado, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci,Canc Ctr, 4200E 9th Ave,Box C238, Denver, CO 80262 USA Univ Colorado 4200 E 9th Ave,Box C238 Denver CO USA 80262 2 USA
Citazione:
Y. Sharma et al., "Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells", MOL CARCINO, 30(4), 2001, pp. 224-236

Abstract

We recently showed the inhibitory effect of a flavonoid antioxidant silymarin, on erbB1-Shc activation in prostate cancer (PCA) DU145 cells. In the present study, we performed more detailed mechanistic and molecular modelingstudies with pure silibinin to assess and define its effect on membrane signaling related to erbB1 activation in human PCA LNCaP and DU145 cells. Studies also were performed to establish the biologic responses toward extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation, cell growth, and DNA synthesis. Treatment of serum-starved cells with various doses ofsilibinin for 2 h followed by I-125-epidermal growth factor (EGF) showed 30-75% inhibition in ligand binding and 55-95% inhibition in its internalization in LNCaP cells and 20-64% and 12-27% inhibition in these two events inDU145 cells. Time-response studies showed similar effects. In further studies, treatment of serum-starved cultures with silibinin followed by EGF showed strong inhibitory effects on membrane and cytoplasmic signaling molecules. In the case of erbB1 activation, silibinin showed a 58-75% decrease in LNCaP and a 40-100% decrease in DU145 cells at 50, 75, and 100-mug/mL doses. Inhibitory effects of silibinin also were evident on ERK1/Z activation (20-80% inhibition) in both cell lines. Treatment of serum-starved cultures with silibinin resulted in 20-40% and 30-55% inhibition of LNCaP and DU145 cell growth, respectively, at similar doses after 1-3 d of treatment, and 10-50% cell death in both cell lines. Under 10% serum conditions, identical silibinin treatments resulted in 20-65% inhibition of cell growth in LNCaP and DU145 cells but did not cause any cell death. Similar doses of silibinintreatments for 24 h also resulted in 25-60%, 35-40%, and 36-50% inhibitionof DNA synthesis when cells were cultured in 10% serum, totally serum starved, and serum starved plus stimulated with EGF, respectively. Molecular modeling of silibinin showed that it is a highly lipophilic compound, suggesting that it interacts with lipid-rich plasma membrane, including binding with erbB1, thereby competing with the EGF-erbB1 interaction. Because the ligand-erbB1 autocrine-loop is causally involved in advanced and androgen-independent PCA, the observed effects of silibinin and its strong lipophilic nature could be useful in developing this agent for the prevention and therapy of PCA. (C) 2001 Wiley-Liss, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 01:54:08