Shirley Robert B, Kaddour-Djebbar Ismail, Patel Dimpu M, Lakshmikanthan Vijayabaskar, Lewis Ronald W, Kumar M Vijay
Department of Urology, Medical College of Georgia, Augusta, GA 30912, USA.
Neoplasia. 2005 Dec;7(12):1104-11. doi: 10.1593/neo.05520.
The proteasome inhibitor Velcade (bortezomib/PS-341) has been shown to block the targeted proteolytic degradation of short-lived proteins that are involved in cell maintenance, growth, division, and death, advocating the use of proteasomal inhibitors as therapeutic agents. Although many studies focused on the use of one proteasomal inhibitor for therapy, we hypothesized that the combination of proteasome inhibitors Lactacystin (AG Scientific, Inc., San Diego CA) and MG132 (Biomol International, Plymouth Meeting, PA) may be more effective in inducing apoptosis. Additionally, this regimen would enable the use of sublethal doses of individual drugs, thus reducing adverse effects. Results indicate a significant increase in apoptosis when LNCaP prostate cancer cells were treated with increasing levels of Lactacystin, MG132, or a combination of sublethal doses of these two inhibitors. Furthermore, induction in apoptosis coincided with a significant loss of IKKalpha, IKKbeta, and IKKgamma proteins and NFkappaB activity. In addition to describing effective therapeutic agents, we provide a model system to facilitate the investigation of the mechanism of action of these drugs and their effects on the IKK-NFkappaB axis.
蛋白酶体抑制剂万珂（硼替佐米/PS - 341）已被证明可阻断参与细胞维持、生长、分裂和死亡的短命蛋白的靶向蛋白水解降解，这支持将蛋白酶体抑制剂用作治疗药物。尽管许多研究聚焦于使用单一蛋白酶体抑制剂进行治疗，但我们推测蛋白酶体抑制剂乳胞素（AG Scientific公司，加利福尼亚州圣地亚哥）和MG132（Biomol International公司，宾夕法尼亚州普利茅斯会议）联合使用可能在诱导细胞凋亡方面更有效。此外，这种方案能够使用单个药物的亚致死剂量，从而减少不良反应。结果表明，当用逐渐增加剂量的乳胞素、MG132或这两种抑制剂的亚致死剂量组合处理LNCaP前列腺癌细胞时，细胞凋亡显著增加。此外，细胞凋亡的诱导与IKKα、IKKβ和IKKγ蛋白的显著丧失以及NFκB活性相一致。除了描述有效的治疗药物外，我们还提供了一个模型系统，以促进对这些药物的作用机制及其对IKK - NFκB轴影响的研究。
