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Thuốc chống loạn thần đã được tái sử dụng chlorpromazine ức chế ung thư đại trực tràng và di căn phổi bằng cách gây ngưng đọng chu kỳ tế bào G2/M, apoptosis và tự thực bào
Tóm tắt
Mặc dù đã có nhiều nỗ lực trong việc phát triển các chiến lược điều trị hiệu quả, ung thư đại trực tràng (CRC) vẫn là một trong những khối u phổ biến và gây tử vong nhất. Tái sử dụng các thuốc đã được phê duyệt là một chiến lược hấp dẫn để phát triển các tác nhân chống ung thư. Một số thuốc chống loạn thần, bao gồm chlorpromazine (CPZ), có hoạt tính chống ung thư. Tuy nhiên, tác động dược lý của CPZ đối với CRC chưa được xác định rõ ràng. Các thử nghiệm MTT, phân tích dòng chảy tế bào, phân tích western blot, mô hình khối u dưới da ở chuột và mô hình di căn phổi qua tiêm tĩnh mạch đuôi đã được sử dụng để điều tra các tác dụng chống ung thư của CPZ đối với CRC và cơ chế tiềm ẩn. Chúng tôi phát hiện rằng CPZ ức chế hiệu quả CRC bằng cách gây ngưng đọng chu kỳ tế bào G2/M và apoptosis. Ngưng đọng chu kỳ tế bào có liên quan đến việc giảm hoạt động của phức hợp cdc2/cyclin B1, bao gồm việc ức chế biểu hiện của cyclin B1, cdc2 và cdc25c, cùng với việc nâng cao mức độ biểu hiện của cdc2 phosphoryl hóa (Tyr15). Hơn nữa, CPZ ức chế tiềm năng màng ti thể và nâng cao mức độ các loài oxy phản ứng trong tế bào ung thư, cho thấy nó kích thích apoptosis nội tại phụ thuộc vào ti thể. CPZ đã chặn dòng chảy tự thực bào và kích thích tự thực bào độc tế bào trong các tế bào CRC. Ngoài ra, CPZ ức chế sự phát triển của khối u trong hai mô hình chuột dưới da mà không gây ra tác dụng phụ rõ rệt. Phân tích sự phong phú của các tế bào miễn dịch trong môi trường khối u cho thấy CPZ không ảnh hưởng đến tỷ lệ của chúng. Hơn nữa, nó ức chế đáng kể di căn phổi của các tế bào CT26 và kéo dài tuổi thọ của chuột. Những phát hiện này chỉ ra rằng việc tái sử dụng CPZ là một chiến lược điều trị mới cho bệnh nhân CRC.
Từ khóa
#ung thư đại trực tràng #chlorpromazine #apoptosis #chu kỳ tế bào #tự thực bào #di căn phổiTài liệu tham khảo
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