Song-Hee Lee, Haeri Lee, Yong-Jin Kwon, Seul-Ki Kim, Eun-Bi Seo, Jie Ohn Sohn, Byung-Hak Kim, Jung-Youl Park, Sang-Kyu Ye
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引用次数: 0
Abstract
Background: Breast cancer remains the leading cause of cancer incidence and mortality among women worldwide, with triple-negative breast cancer (TNBC) posing significant treatment challenges. The dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway contributes to tumor progression, making it a potential therapeutic target. Chalcones, known for their diverse biological activities, including anti-cancer effects, hold promise for drug development. This study explores the anti-cancer activity of (E)-4-(3-(2-(benzyloxy)-6-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzoic acid (chalcone-9), a novel chalcone derivative.
Methods: The cytotoxic effects of chalcone-9 were evaluated in breast cancer cell lines, including TNBC lines MDA-MB-231 and MDA-MB-468. Western blotting and qRT-PCR were used to analyze the impact on JAK1, JAK2, STAT1, and STAT3 activation and their downstream gene expression. In silico molecular docking analysis was conducted to determine whether chalcone-9 can interact with JAK1 and JAK2. A wound healing assay was used to observe the effect of chalcone-9 on tumor cell migration, and flow cytometry was employed to analyze whether chalcone-9 inhibits tumor cell cycle progression and induces apoptosis. The expression of apoptosis markers was also assessed.
Results: Chalcone-9 exhibited dose-dependent cytotoxicity in breast cancer cell lines, with TNBC cells showing higher sensitivity. Chalcone-9 effectively inhibited the activation of JAK1, JAK2, STAT1, and STAT3, outperforming conventional JAK/STAT inhibitors. The structure of chalcone-9 was confirmed to stably interact with JAK1 and JAK2 proteins. It also suppressed STAT1 and STAT3 target gene expression, reduced tumor cell migration, and induced apoptosis, as evidenced by PARP and caspase cleavage and decreased survivin levels.
Conclusions: Chalcone-9 demonstrates significant anti-cancer activity, particularly against TNBC. By targeting the JAK/STAT pathway and promoting apoptosis, chalcone-9 emerges as a promising therapeutic candidate for aggressive breast cancers.
期刊介绍:
Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures.
Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology.
Studies of plant extracts are not suitable for Pharmacological Reports.