Metal-based 2,3-indolinedione derivatives as proteasome inhibitors and inducers of apoptosis in human cancer cells.

Pengfei Zhang,Xin Li,Caifeng Bi,Q Ping Dou,Nan Zhang,Sara M Schmitt,Yuhua Fan

doi:10.3892/ijmm.2014.1838

Abstract

Proliferation and apoptotic pathways are tightly regulated in cells by the ubiquitin-proteasome system (UPS). Alterations in the UPS may result in cellular transformation or other pathological conditions. The proteasome is indeed often found to be overactive in cancer cells. It has been reported that 2,3-indolinedione (L), which exists in marine organisms, as well as in mammals, is a proteasome inhibitor. Studies have shown that metal-based complexes inhibit proteasome activity and induce apoptosis in certain human cancer cells. In the current study, we synthesized six novel metal-based complexes with derivatives of 2,3-indolinedione: [Cd (C15H11O3N2) (CH3COO)] (C1), [Cd (C15H11O2N2) (CH3COO)] (C2), [Co (C15H9O4N2) (CH3COO)] (C3), [Co (C15H11O2N2) (CH3COO)] (C4), [Zn (C19H14O3N3) (CH3COO)] (C5) and [Zn (C17H13O3N2) (CH3COO)] (C6). We sought to characterize and assess the proteasome inhibitory and anti-proliferative effects of these metal-based complexes in human breast (MDA-MB-231) and prostate (LNCaP and PC-3) cancer cells, in order to determine whether specific structures contribute to the inhibition of tumor proteasome activity and the induction of apoptosis. The results revealed that the complexes, C1, C3 and C5, but not their counterparts, C2, C4 and C6, inhibited the chymotrypsin-like activity of the human cancer cellular 26S proteasome; in addition, these complexes promoted the accumulation of the proteasome target protein, Bax, inhibited cell growth and induced apoptosis in a concentration- and time-dependent manner due to their unique structures. Our data suggest that the study of metal-based complexes, including aromatic ring structures with electron-attracting groups, may be an interesting research direction for the development of anticancer drugs.

Highlights

The ubiquitin-proteasome system (UPS) is a major pathway for intracellular protein degradation and regulates a number of key cellular processes
Considering the importance of the UPS and the properties of 2,3-indolinedione, we aimed to investigate whether 2,3-indolinedione derivatives have the ability to inhibit proteasome activity, and whether structure is an essential factor affecting antitumor activity
Compounds C1-C6 were synthesized by the laboratory at the Ocean University of China, Qingdao, China. 3-(4,5-Dimethylthiazol‐2‐yl)-2,5-diphenyltetrazolium bromide (MTT), dimethyl sulfoxide (DMSO) and other chemicals were purchased from Sigma-Aldrich

Summary

Introduction

The ubiquitin-proteasome system (UPS) is a major pathway for intracellular protein degradation and regulates a number of key cellular processes. Its target proteins include a broad array of regulatory proteins that play important roles in cell cycle progression, cell development and differentiation, DNA damage response and tumorgenesis. This system allows the cells to modulate their protein expression patterns in response to changing physiological conditions and plays a critical role in health and disease [1,2]. The proteasome is a massive multicatalytic protease responsible for degrading a large number of cellular proteins. Several studies have shown that the inhibition of the proteasomal chymotrypsin-like activity results in the accumulation of several target proteins and the induction of apoptosis in various types of tumor cells [5,6]

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