Park Cheol, Kim Gi Young, Kim Gun Do, Lee Won Ho, Cheong Jae Hun, Kim Nam Deuk, Bae Song-Ja, Jung Jee H, Choi Yung Hyun
Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Korea.
Oncol Rep. 2006 Jul;16(1):171-6.
Dideoxypetrosynol A, a polyacetylene from the marine sponge Petrosia sp., is known to exhibit significant selective cytotoxic activity against a small panel of human tumor cell lines, the mechanisms of which however, are poorly understood. The aim of the present study was to further elucidate the possible mechanisms by which dideoxypetrosynol A exerts its anti-proliferative action in cultured human monocytic leukemia U937 cells. We observed that the proliferation-inhibitory effect of dideoxypetrosynol A was due to the induction of G1 arrest in the cell cycle, the effects of which were associated with up-regulation of cyclin D1 and down-regulation of cyclin E, in a concentration-dependent manner without any change in cyclin-dependent-kinases (Cdks) expression. Dideoxypetrosynol A markedly induced the levels of Cdk inhibitor p16/INK4a expression. Furthermore, down-regulation of phosphorylation of retinoblastoma protein (pRB) by this compound was associated with enhanced binding of pRB and transcription factor E2F-1. Overall, our results demonstrate a combined mechanism involving the inhibition of pRB phosphorylation and induction of p16 as targets for dideoxypetrosynol A, may explain some of its anti-cancer effects.
双脱氧岩藻醇A是一种从海洋海绵Petrosia sp.中提取的聚乙炔，已知其对一小部分人类肿瘤细胞系具有显著的选择性细胞毒性活性，但其作用机制尚不清楚。本研究的目的是进一步阐明双脱氧岩藻醇A在培养的人单核细胞白血病U937细胞中发挥抗增殖作用的可能机制。我们观察到，双脱氧岩藻醇A的增殖抑制作用是由于细胞周期中G1期阻滞的诱导，其作用与细胞周期蛋白D1的上调和细胞周期蛋白E的下调有关，呈浓度依赖性，而细胞周期蛋白依赖性激酶（Cdks）的表达没有任何变化。双脱氧岩藻醇A显著诱导细胞周期蛋白依赖性激酶抑制剂p16/INK4a的表达水平。此外，该化合物对视网膜母细胞瘤蛋白（pRB）磷酸化的下调与pRB和转录因子E2F-1结合的增强有关。总体而言，我们的结果表明，双脱氧岩藻醇A通过抑制pRB磷酸化和诱导p16作为靶点的联合机制，可能解释了其一些抗癌作用。
