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SR16388: chất chống tăng sinh mạch steroid với hiệu ứng ức chế mạnh mẽ đối với sự phát triển khối u trong cơ thể sống
Tóm tắt
Sự hình thành mạch là một trong những quá trình chủ yếu kiểm soát tăng trưởng và di căn của khối u. Các chất ức chế sự hình thành mạch đã được nhắm đến để điều trị nhiều loại ung thư trong hơn 2 thập kỷ qua. Chúng tôi đã phát triển một lớp hợp chất steroid mới nhằm mục tiêu ngăn chặn quá trình hình thành mạch trong các mô ung thư. Hợp chất chính của chúng tôi, SR16388, là một tác nhân chống hình thành mạch mạnh mẽ với độ gắn kết cao đến thụ thể estrogen-α (ER-α) và -β (ER-β) trong phạm vi nanomolar. Hợp chất này đã ức chế sự gia tăng của các tế bào nội mô vi mạch người (HMVEC) và nhiều loại tế bào ung thư người khác nhau trong môi trường nuôi cấy. SR16388 đã ức chế sự hình thành mạch thai kỳ như được đo bằng thử nghiệm màng niệu huyết (CAM) của phôi gà. Mật độ mạch máu trong CAM đã giảm đáng kể sau khi các phôi được điều trị với 3 μg/CAM SR16388 trong 24 giờ. SR16388 với liều 2 μM đã ngăn chặn sự hình thành ống trong Matrigel sau khi các tế bào HMVEC được điều trị trong 8 giờ. Trong thí nghiệm buồng Boyden điều chỉnh, SR16388 đã ức chế sự di cư của các tế bào HMVEC tới 80% tại nồng độ 500 nM. Sử dụng mô hình buồng Z-fibrin in vivo mới, chúng tôi đã chứng minh rằng SR16388 với liều uống 3 mg/kg một lần mỗi ngày trong 12 ngày đã ức chế một cách đáng kể độ dày của mô hạt (GT) và mật độ mạch máu của GT so với nhóm đối chứng. Quan trọng hơn, SR16388 đã giảm điều hòa các yếu tố phiên mã pro-angiogenic, yếu tố gây thiếu oxy 1α (HIF-1α) và yếu tố truyền tín hiệu và kích hoạt phiên mã 3 (STAT3) trong các tế bào ung thư phổi không nhỏ (NSCLC). Tất cả những tác động này của SR16388 có thể dẫn đến giảm vascularization và sự phát triển của khối u trong cơ thể sống.
Từ khóa
#angiogenesis #SR16388 #inhibitor #cancer #endothelial cells #HMVEC #NSCLCTài liệu tham khảo
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