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.