Sự kích thích tuần tự của thảm họa phân bào tiếp theo là apoptosis trong các tế bào ung thư máu người MOLT4 bởi imidazoacridinone C-1311

Springer Science and Business Media LLC - Tập 12 - Trang 2245-2257 - 2007
Anna Skwarska1, Ewa Augustin1, Jerzy Konopa1
1Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, Gdansk, Poland

Tóm tắt

Imidazoacridinone C-1311 là một chất chống u mục tiêu DNA đang trong giai đoạn thử nghiệm lâm sàng giai đoạn II. Trong nghiên cứu này, chúng tôi đã làm rõ trình tự phản ứng chết tế bào do C-1311 trong các tế bào bạch cầu người MOLT4 với nồng độ thuốc (30 nM) gây ức chế gần như hoàn toàn sự phát triển tế bào sau 48 giờ. Các phản ứng sớm (6-12 giờ) bao gồm sự tích tụ tạm thời của các tế bào tại ranh giới G2/M tiếp theo là sự gia tăng tạm thời của một số dấu hiệu phân bào. Các nỗ lực phân bào chủ yếu đã bất thường, dẫn đến nhiều tế bào đa nhân (đạt đỉnh tại 24-39 giờ và suy giảm rõ rệt ở các thời điểm sau). Những sự kiện này, cho thấy thảm họa phân bào, không liên quan đến cái chết tế bào ngay lập tức. Tỷ lệ tế bào hoại tử không vượt quá 3%. Hơn nữa, các biểu hiện cổ điển của apoptosis rất ít ỏi ở 24 giờ và sự tiến triển của chúng rõ ràng theo sau sự suy giảm trong tỷ lệ tế bào phân bào và tế bào đa nhân. Việc định lượng một số dấu hiệu apoptotic (bao gồm sự phơi bày phosphatidylserine, các đứt gãy DNA apoptotic, rối loạn chức năng ty thể, kích hoạt caspase và tính toàn vẹn màng tế bào) cho thấy có sự tiến triển đáng kể và sự chuyển tiếp từ apoptosis sớm sang muộn vào các thời điểm sau. Tại 72 giờ, hơn 80% tế bào đã apoptotic. Tóm lại, những phát hiện này cho thấy thảm họa phân bào do C-1311 gây ra không phải là sự kiện chết cuối cùng mà là một bước làm bùng phát các phản ứng apoptotic trễ, mặc dù rất mạnh mẽ.

Từ khóa

#imidazoacridinone C-1311 #thảm họa phân bào #apoptosis #tế bào bạch cầu người #MOLT4

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