Novel Copper Complexes That Inhibit the Proteasome and Trigger Apoptosis in Triple-Negative Breast Cancer Cells

Abstract

Five innovative ternary copper(II) complexes [Cu(OH-PIP)(Phe)Cl](1), [Cu(OH-PIP)(Gly)(H 2 O)]NO 3 • 2H 2 O (2), [Cu(OH-PIP)(Ala)(Cl)]•H 2 O (3), [Cu(OH-PIP)(Met)]PF 6 •2H 2 O (4), and [Cu(OH-PIP)(Gln)(H 2 O)](Cl)• 3H 2 O (5) have been synthesized and characterized by infrared spectroscopy, elemental analysis, and single crystal X-ray diffraction analysis. X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration. The complexes have been screened for cytotoxicity against human breast cancer cell lines MCF-7, MDA-MB-231, and CAL-51.The best anticancer activity is obtained with triple-negative breast cancer CAL-51 and MDA-MB-231 cell lines, with IC 50 values in the range of 0.082−0.69 μM. Importantly, the copper compounds were more effective than carboplatin at triggering cell death. Mechanistically, the complexes inhibit proteasomal chymotrypsin-like activity, and docking studies reveal their 20S proteasome binding sites. As a consequence, they cause the accumulation of ubiquitinated proteins, inhibit cell proliferation, and induce apoptosis. In addition, these copper complexes decrease the stemness of triple-negative breast cancer cells and have synergistic effects with CBP on TNBC cells, indicating their great potential as a novel therapy for triple-negative breast cancer.

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

“…USP14 promotes tumor growth by regulating DNA damage response or ER stress-mediated autophagy in non-small cell lung cancer cells ( Moghadami et al, 2020 ; Sharma and Almasan, 2020 ). Alone this line, several compounds targeting UCHL5 and USP14 have been developed, including b-AP15 ( D'Arcy et al, 2011 ), VLX1570 (b-AP15 analog) ( Wang et al, 2016 ), AC17 (curcumin analog) ( Zhou et al, 2013 ), and various metal-based complexes ( Liu et al, 2014b ; Chen et al, 2018a ; Li et al, 2019a ). Inhibition of deubiquitinating activity of USP14 and UCHL5 by b-AP15 rescues the protein level of TP53 in tumors from Tp53 −/− mice ( Ma et al, 2020 ).…”

Anticancer Activity and Mechanism of Action Evaluation of an Acylhydrazone Cu(II) Complex toward Breast Cancer Cells, Spheroids, and Mammospheres

“…Based on previous studies showing the interaction of copper complexes with 20S proteasome [46,47] it was decided to analyze the possibility of interaction of CuHL with this protein complex. the copper complexes with 20S proteasome was proposed by molecular docking.…”

“…[55] Besides, Li et al published five aminopolypyridine-copper complexes that displayed the proteasomeinhibitory and apoptosis-inducing activities on triple negative breast cancer cells. [47] 3D studies…”

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple‐Negative Breast Cancer through Inhibition of mTOR Signaling

“…For the apoptotic pathway induced by 8 c , 8 e and 8 i to be investigated, the expression levels of apoptotic proteins Bax and Bcl‐2, executioner caspase‐3, and poly ADP ribose polymerase (PARP, an apoptosis marker) were evaluated. When Bax expression is high, cells proceed to apoptosis, whereas when Bcl‐2 is produced in excess, cells are protected from apoptosis [26] . As shown in Figure 5, 8 c , 8 e and 8 i markedly enhanced the expression levels of the pro‐apoptosis protein Bax but suppressed the levels of pro‐survival protein Bcl‐2.…”