RESUMO
Therapeutic targeting of the nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP1) with PARP inhibitors (PARPis) in patients with a homologous recombination (HR)- deficient phenotype based on the mechanism of synthetic lethality has been shown tremendous success in cancer therapy. With the clinical use of various PARPis, emerging evidence has shown that some PARPis offer hope for breakthroughs in triple-negative breast cancer (TNBC) therapy, regardless of HR status. However, similar to other conventional cytotoxic drugs, PARPis are also subject to the intractable problem of drug resistance. Notably, acquired resistance to PARPis caused by point mutations in the PARP1 protein is hard to overcome with current strategies. To explore modalities to overcome resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted chimaera (PROTAC) to degrade mutant PARP1 in TNBC. Here, we investigated a PARP1 PROTAC termed "NN3â³, which triggered ubiquitination and proteasome-mediated degradation of PARP1. Moreover, NN3 degraded PARP1 with resistance-related mutations. Interestingly, compared with other reported PARP1 degraders, NN3 exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. Furthermore, NN3 showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.
Assuntos
Antineoplásicos , Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Linhagem Celular Tumoral , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteólise , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , FemininoRESUMO
A new taraxer-based triterpenoid ester, taraxer-14-en-30-al-3ß-O-palmitate(1), was isolated from the whole plant of Wedelia trilobata, along with six known compounds, ent-kaur-16-en-19-oic acid(2), 16α-hydroxy-ent-kauran-19-oic acid(3), tara-xerol(4), ß-amyrin(5), 1ß-acetoxy-4α, 9α-dihydroxy-6ß-isobutyroxyprostatolide(6), and stigmasterol(7). Their structures were elucidated with use of a combination of spectroscopic techniques(IR, HR-ESI-MS, 1 D, 2 D NMR data) and chemical methods.
Assuntos
Triterpenos , Wedelia , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Two new glycosides including an alcohol glycoside and a phenolic glycoside: hexyl-1-O-α-d-arabinofuranosyl-(1 â 6)-ß-d-glucopyranoside (1), 4-hydroxypropiophenone-4-O-ß-d-glucopyranosyl(1 â 6)-ß-d-glucopyranoside(2), along with six known naphthalenyl glucosides (3-8) were isolated from green walnut husks of Juglans mandshurica, and their structures were elucidated on the basis of spectroscopic studies. All compounds were evaluated for their inhibitory effects on tumour cells (BGC-823, HepG-2, MCF-7). The results showed that new compounds 1 and 2 had superior inhibitory activity in comparison with other naphthalenyl glucosides.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Glicosídeos/química , Juglans/química , Nozes/química , Álcoois/análise , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Glucosídeos/análise , Glucosídeos/química , Glicosídeos/isolamento & purificação , Humanos , Hidroxipropiofenona , Estrutura Molecular , Fenóis/análise , Extratos Vegetais/análise , Extratos Vegetais/química , Análise Espectral , Células Tumorais CultivadasRESUMO
A new triterpenoid ester, 7ß-hydroxyl-hop-22(29)-en-3ß-O-palmitate (1), was isolated from the stems and leaves of Scurrula parasitica parasitic on Nerium indicum, along with nine known compounds, uvaol (2), 3-epi-ursolic acid (3), 3ß-hydroxyl-hop-22(29)-ene (4), 3ß, 15α-dihydroxyl-lup-20(29)-ene (5), lup-20(29)-en-3-O-α-D-glucoside (6), stigmasterol-3-O-ß-D-glucoside (7), digitoxin-3-O-α-D-glucoside (8), behenic acid (9), octacosyl alcohol (10). Their structures were elucidated using a combination of 1D and 2D NMR techniques (COSY, HMQC, and HMBC) and HR-ESI-MS analyses. Compounds 2-10 were isolated from this plant for the first time.
Assuntos
Loranthaceae/química , Triterpenos/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Folhas de Planta/química , Caules de Planta/química , Saponinas/isolamento & purificação , Ácido UrsólicoRESUMO
A new steroidal ester, beta-rosaterol palmitate (1) along with ten known compounds, uvaol(2), 3-epi-ursolic acid (3), 2alpha, 3beta, 24-trihydroxyolean-12-en-28-oic acid (4), 2alpha, 3alpha, 24-trihydroxyurs-12-en-28-oic acid (5), 2alpha, 3alpha, 24-trihydroxyolean-12-en-28-oic acid (6), 2alpha, 3alpha, 24-trihydroxyolean-12-en-28-oic acid-28-O-beta-D-glucopyranosyl ester (7), (Z)-9-hexadecenoic acid (8), octacosyl alcohol (9), beta-sitosterol (10) and beta-daucosterol (11), has been isolated from the stems and leaves of Vitex trifolia. Their structures were elucidated using a combination of 1D and 2D NMR techniques (COSY, HMQC, and HMBC)and HR-ESI-MS analyses. Compounds 2-7 were isolated from this plant for the first time.
