Mechanisms of proteasome inhibitor action and resistance in cancer

被引：249

作者：

McConkey, David J. ^{[1
]}

Zhu, Keyi

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA

来源：

DRUG RESISTANCE UPDATES | 2008年 / 11卷 / 4-5期

关键词：

Pancreatic cancer; Pancreas; Autophagy; NF kappa B; Unfolded protein response (UPR); elf2; alpha; Grp78; BIP; p53; Bcl2; family;

D O I：

10.1016/j.drup.2008.08.002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Proteasome inhibitors (PIs), such as bortezomib, carfilzomib or NPI-0052, have excellent clinical activity in patients with multiple myeloma and mantle cell lymphoma, and they are currently being evaluated in combination with other agents in patients with solid tumors. Although they exert broad effects on cancer cells, their ability to (1) stabilize pro-apoptotic members of the BCL-2 fan-lily, (2) inhibit the two major pathways leading to NF kappa B activation, and (3) cause the build-up of misfolded proteins appear to be particularly important. In addition, PIs may disrupt tumor-stromal interactions that drive NF kappa B activation and angiogenesis and in such a way sensitize cancer cells to other agents. Still, drug resistance ultimately emerges in all tumors that initially respond to PIs. This review provides an overview of the current thinking about how PIs may kill cancer cells exemplified for pancreatic cancer and the possible mechanisms involved in resistance to PIs. (C) 2008 Published by Elsevier Ltd.

引用

页码：164 / 179

页数：16

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