RESUMEN
Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine-encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases.
Asunto(s)
Atrofia Bulboespinal Ligada al X/genética , Curcumina/análogos & derivados , Proteínas de Unión al ADN/genética , Proteínas de Drosophila/genética , Trastornos Musculares Atróficos/genética , Factor 1 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/genética , Receptores Androgénicos/genética , Factores de Transcripción/genética , Expansión de Repetición de Trinucleótido/genética , Animales , Atrofia Bulboespinal Ligada al X/tratamiento farmacológico , Atrofia Bulboespinal Ligada al X/patología , Curcumina/administración & dosificación , Curcumina/química , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Técnicas de Silenciamiento del Gen , Factores de Transcripción del Choque Térmico , Humanos , Ratones , Trastornos Musculares Atróficos/tratamiento farmacológico , Trastornos Musculares Atróficos/patología , Estrés Oxidativo/efectos de los fármacos , Péptidos/genética , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Agregación Patológica de Proteínas/genética , Pliegue de Proteína/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/administración & dosificaciónRESUMEN
In a continuing study of curcumin analogues as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogues classified into four series: monophenyl analogues (series A), heterocycle-containing analogues (series B), analogues bearing various substituents on the phenyl rings (series C), and analogues with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells, seven only against LNCaP, and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogues with better anti-prostate cancer activity.
Asunto(s)
Antineoplásicos/síntesis química , Curcumina/análogos & derivados , Curcumina/síntesis química , Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Curcumina/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Genes Reporteros , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Masculino , Mutación , Neoplasias Hormono-Dependientes , Neoplasias de la Próstata , Receptores Androgénicos/genética , Relación Estructura-Actividad , Activación Transcripcional , TransfecciónRESUMEN
4-Ethoxycarbonylethyl curcumin (ECECur) (3) is a current drug candidate for the treatment of prostate cancer. Due to problems inherent in the tautomerism of ECECur, 4-fluoro-4-ethoxycarbonylethyl curcumin (4) and 4-ethoxycarbonylethylenyl curcumin (5) were designed and synthesized. These two target compounds and their synthetic intermediates (4-9) were evaluated for their inhibitory activity against androgen receptor transcription in LNCaP and PC-3 prostate cancer cell lines. While the enol-keto analogs showed varying anti-androgen potencies, the di-keto analogs showed no activity. Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-AR activity of 4-ethoxycarbonylethylenyl curcumin, but a negative impact on the activity of ECECur. With potent anti-AR activity, di-tetrapyranylated 4-ethoxycarbonylethylenyl curcumin (9), which exists in only one form, is a good drug lead for further structural modification. Based on the SAR information obtained from the above study, five new compounds were designed and subsequently synthesized. Among them, compound 10 was found to be the most potent anti-AR agent and is considered to be a promising drug candidate for the treatment of prostate cancer.
Asunto(s)
Antineoplásicos/farmacología , Curcumina/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Curcumina/química , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Neoplasias de la Próstata/patología , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
Fifteen new diarylheptanoids were synthesized and evaluated for antagonistic activity against androgen receptor (AR)-mediated reporter gene transcription using DU145, PC-3, and LNCaP prostate cancer cell lines. Most compounds showed activity in a 5alpha-dihydrotestosterone (DHT)-induced reporter gene expression assay in DU145 cells transfected with wild-type AR. Ten compounds (5, 8, 10, 14-15, and 18-22) were equipotent with hydroxyflutamide (HF), the anti-androgen currently available for the treatment of prostate cancer. However, except for compounds 5 and 10, none of the tested compounds was significantly effective in attenuating DHT-induced reporter gene expression in LNCaP cells, which contain endogenous mutant AR.