Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells

Chen, Xin; Zhang, Xiaolan; Chen, Jinghong; Yang, Qianqian; Yang, Li; Xu, Dacai; Zhang, Peiquan; Wang, Xuejun; Liu, Jinbao

doi:10.1016/j.ejphar.2017.09.003

Cited by 56 publications

(43 citation statements)

References 47 publications

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“…In agreement with the suggested contribution of mitochondria to Me 2 NNMe 2 activity, HCT-116 cells with a BAX knockout 18 were (in contrast to Triapine) significantly less sensitive to the methylated derivative (Fig. 3c ).…”

Section: Resultssupporting

confidence: 84%

“…The following human cell models were used in this study: the colon carcinoma cell lines SW480 (obtained from the American Tissue Culture Collection) as well as HCT-116 and its respective subline with BAX knockout (obtained from B. Vogelstein, John Hopkins University, Baltimore 18 ). SW480 cells were cultured in MEME and HCT-116 cell lines in McCoy’s 5a Medium (from Sigma-Aldrich, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

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The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

et al. 2018

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Due to their high biological activity, thiosemicarbazones have been developed for treatment of diverse diseases, including cancer, resulting in multiple clinical trials especially of the lead compound Triapine. During the last years, a novel subclass of anticancer thiosemicarbazones has attracted substantial interest based on their enhanced cytotoxic activity. Increasing evidence suggests that the double-dimethylated Triapine derivative Me2NNMe2 differs from Triapine not only in its efficacy but also in its mode of action. Here we show that Me2NNMe2- (but not Triapine)-treated cancer cells exhibit all hallmarks of paraptotic cell death including, besides the appearance of endoplasmic reticulum (ER)-derived vesicles, also mitochondrial swelling and caspase-independent cell death via the MAPK signaling pathway. Subsequently, we uncover that the copper complex of Me2NNMe2 (a supposed intracellular metabolite) inhibits the ER-resident protein disulfide isomerase, resulting in a specific form of ER stress based on disruption of the Ca2+ and ER thiol redox homeostasis. Our findings indicate that compounds like Me2NNMe2 are of interest especially for the treatment of apoptosis-resistant cancer and provide new insights into mechanisms underlying drug-induced paraptosis.

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Section: Resultssupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

et al. 2018

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“…Hinokitiol is a tropolone-based phenolic component isolated from Cupressaceae heartwood and its anticancer effects and antimicrobial activity have been well-documented (Inoue et al, 2020;Wu et al, 2020). In addition, the hinokitiol copper complex (CuHK) has been confirmed as an inhibitor of the 19S DUB, but not the CT-like activity of the 20S proteasome (Chen et al, 2017). This function of CuHK on DUB inhibition causes accumulation of ubiquitinated proteins and GFPu in cancer cells (A549 and K562) and HEK293 cells, respectively (Chen et al, 2017).…”

Section: Cuhkmentioning

confidence: 99%

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

Chen

Dou

Liu

et al. 2021

Front. Mol. Biosci.

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Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin–proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug–drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.

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“…Copper compounds, similar to other anti-cancer metals such as gold, silver, and ruthenium, are known as inducers of apoptosis, especially in cancer cells [4,5,6,7]. Additionally, copper complexes with phenanthroline derivatives with various alkyl chains were shown to have not only anti-tumour activity, but also anti-metastatic and anti-angiogenic activity [8].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Anticancer Properties of Copper Metallodendrimers

et al. 2019

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Newly synthesized carbosilane copper dendrimers (CCD) with chloride and nitrate surface groups seem to be good candidates to be used as gene and drug carriers in anti-cancer therapy, due to their properties such as size and surface charge. Copper attached to the nanoparticles is an important element of many biological processes and recently their anti-cancer properties have been widely examined. Zeta size and potential, transmission electron microscopy (TEM), circular dichroism (CD), analysis of haemolytic activity, and fluorescence anisotropy techniques were used to characterize copper dendrimers. Additionally, their cytotoxic properties toward normal (PBMC) and cancer (1301; HL-60) cells were examined. All tested dendrimers were more cytotoxic against cancer cells in comparison with normal cells.

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Hinokitiol copper complex inhibits proteasomal deubiquitination and induces paraptosis-like cell death in human cancer cells

Cited by 56 publications

References 47 publications

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

In Vitro Anticancer Properties of Copper Metallodendrimers

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