نوع مقاله : مقاله پژوهشی کامل
نویسندگان
گروه زیست شناسی، دانشگاه پیام نور، تهران، ایران
چکیده
سرطان پستان سهگانه منفی (TNBC) فاقد گیرندههای قابل هدف درمانی است و شیمیدرمانی متداول، علیرغم سمیت بالا و مقاومت اکتسابی، تنها گزینه استاندارد درمانی محسوب میشود. محورهای سیگنالینگ NF-κB و STAT3 در TNBC بهطور مداوم فعال هستند و بهعنوان محرکهای انکوژنیک متقابل شناخته میشوند. ازاینرو، مهار همزمان آنها یک راهبرد درمانی جذاب محسوب میگردد. بتا-سیتوسترول، فیتوسترول غالب دانههای Allium cepa، خواص ضدتکثیری گستردهای نشان میدهد؛ با این حال، توانایی آن در تعامل همزمان با NFKB1 و STAT3 بهصورت سیستماتیک بررسی نشده است. پروفایلسازی GC–MS روغن دانه A. cepa، بتا-سیتوسترول را بهعنوان ترکیب اصلی با سهم ۸۰٪ شناسایی کرده است. آنالیز محاسباتی ADMET، اعتبارسنجی ایمونوسیتوشیمیایی اهداف از پایگاه داده Human Protein Atlas، و داکینگ مولکولی با AutoDock Vina علیه NFKB1 (PDB: 5AX3) و STAT3 (PDB: 7LET) انجام گرفت. فعالیت ضدسرطانی در سلولهای MDA-MB-231 از طریق سنجش MTT ارزیابی شد و مکانیسم آپوپتوز با فلوسیتومتری Annexin V-FITC/PI مشخص گردید. بتا-سیتوسترول دارای پروفایل دارویی مطلوب، توزیع پیشبینیشده در میتوکندری، و فقدان جهشزایی ژنوتوکسیک گزارش شد. داکینگ انرژیهای اتصال 7.0- و 6.7- کیلوکالری بر مول را بهترتیب برای STAT3 و NFKB1 نشان داد که عمدتاً از طریق برهمکنشهای هیدروفوبیک ایجاد میشوند. سنجش MTT سمیت سلولی وابسته به غلظت را آشکار کرد (IC₅₀ = 39.56 µM؛ 72h؛ F = 113.8، p < 0.0001). فلوسیتومتری القای معنادار آپوپتوز اولیه (30.7 ± 2.5%) و آپوپتوز دیررس (20.3 ± 4.4%) را در مقایسه با سطوح پایه ناچیز در گروه کنترل تأیید کرد. بتا-سیتوسترول همراه با قدرت اتصال محاسباتی دوگانه به NFKB1 و STAT3، فعالیت آپوپتوزی قوی در سلولهای TNBC از خود نشان میدهد و بدینترتیب پایه مکانیستی برای توسعه ترجمانی بیشتر آن بهعنوان داوطلب درمانی دو محوره در سرطان پستان سهگانه منفی فراهم میآورد.
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