Dépôt numérique

Proliferative and androgenic effects of indirubin derivatives in LNCaP human prostate cancer cells at sub-apoptotic concentrations

Rivest, Patricia; Renaud, Martin et Sanderson, J. Thomas ORCID logoORCID: https://orcid.org/0000-0002-3190-2811 (2011). Proliferative and androgenic effects of indirubin derivatives in LNCaP human prostate cancer cells at sub-apoptotic concentrations Chemico-Biological Interactions , vol. 189 , nº 3. pp. 177-185. DOI: 10.1016/j.cbi.2010.11.008.

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Certain indirubin derivatives are potent cyclin-dependent kinase (CDK) and glycogen synthase kinase (GSK-3 beta) inhibitors and may be effective against various cancers. We evaluated the effects of aloisine A, alsterpaullone, aminopurvalanol, 6-Br-indirubin-3'-oxime, kenpaullone, olomoucine and roscovitine on cell proliferation, prostate-specific antigen (PSA) expression, androgen receptor (AR) activation, and GSK-3 beta and beta-catenin expression in androgen-dependent LNCaP human prostate cancer cells. Effects were also evaluated in MDA-kb2 human breast cancer cells containing an AR-responsive luciferase construct. Steroid-deprived LNCaP cells were exposed to indirubins dihydrotestosterone (DHT 0.1 nM) and cell proliferation was assessed by MIT assay after 120h. PSA expression was determined by real-time quantitative RT-PCR after 24h. Cytoplasmic and nuclear GSK-3 beta/beta-catenin expression and phosphorylation status was determined by Western blotting. Effects on MDA-kb2 luciferase expression were determined after 24 h using Steady-Glo (Promega). Indirubin-3'-oxime, 6-Br-indirubin-3'-oxime, alsterpaullone and kenpaullone increased LNCaP cell proliferation and PSA expression (0.03-1 mu M; apoptosis occurred > 1 mu M), whereas aminopurvalanol significantly (p < 0.05) reduced DHT-stimulated PSA expression (31%) at 1 nM. The other indirubin derivatives had no effect. The same was observed for induction of AR-dependent MDA-kb2 luciferase expression. Kenpaullone (1,3 p,M) decreased the active- and increased the inactive form of cytoplasmic GSK-3 beta, and increased nuclear AR and beta-catenin accumulation. Flutamide (10 p,M), unexpectedly, also strongly increased nuclear beta-catenin accumulation. Indirubin derivatives that were potent GSK-3 beta inhibitors (relative to CDK1) stimulated LNCaP cell proliferation and other androgenic responses, suggesting (in a cancer treatment context) these compounds may increase AR-dependent prostate cancer growth if not used within an appropriate therapeutic dose-range.

Type de document: Article
Mots-clés libres: LNCaP cells; MDA-kb2 cells; GSK-3β; Androgenic; β-Catenin; Indirubins
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 29 mars 2024 21:02
Dernière modification: 29 mars 2024 21:02
URI: https://espace.inrs.ca/id/eprint/15114

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