Abstract
BackgroundIn recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. In this study, a novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells.MethodsMultiple molecular experiments including Flow cytometry, Western blot, Immunofluorescence, Tracker staining, Transmission Electron Microscopy and Molecular docking simulation were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo.ResultsCTB induced apoptosis via collapse of mitochondrial membrane potential (MMP), ROS production, Bax mitochondrial aggregation as well as cytochrome c release, indicating that CTB-induced apoptosis was associated with mitochondrial pathway in human hepatoma cells. Mechanistic study revealed that ROS-related mitochondrial translocation of p53 was involved in CTB-mediated apoptosis. Simultaneously, elevated mitochondrial Drp1 levels were also observed, and interruption of Drp1 activation played critical role in p53-dependent apoptosis. CTB also strongly suppressed the growth of liver cancer xenografts in vivo.ConclusionIn human hepatoma cells, CTB primarily induces mitochondrial dysfunction and promotes accumulation of ROS, leading to activation of Drp1. These stimulation signals accelerate mitochondrial accumulation of p53 and lead to the eventual apoptosis. Our research shows that CTB merits further evaluation as a chemotherapeutic agent for the treatment of Hepatocellular carcinoma (HCC).
Highlights
In recent years, copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity
The cytotoxicity of Cu[(ttpy-tpp)Br2] Br (CTB) on human liver cancer cells (HepG2, SMMC-7721, BEL-7402, Huh-7, Hep3B) and human hepatocytes (LO2) at 24 h was tested by MTT analysis, showing that LO2 cells were less sensitive to CTB since the IC50 at 24 h was higher than that of other hepatoma cells respectively (Fig. 1b)
Through the detection of Rhodamine 123 staining in hepatoma cells, we found that Pifthrin-μ attenuated the opening of mitochondrial permeability transition pore (mPTP), suggesting that mitochondrial p53 could further aggravate mitochondrial damage (Fig. 5f)
Summary
Copper complexes have gradually become the focus of potential anticancer drugs due to their available redox properties and low toxicity. A novel mitochondrion-targeting copper (II) complex, [Cu (ttpy-tpp)Br2] Br (simplified as CTB), is first synthesized by our group. CTB with tri-phenyl-phosphine (TPP), a targeting and lipophilic group, can cross the cytoplasmic and mitochondrial membranes of tumor cells. The present study aims to investigate how CTB affects mitochondrial functions and exerts its anti-tumor activity in hepatoma cells. Due to the remarkable efficacy of metal drugs in the treatment of various cancers, the study of metal complexes has long been a hot topic [4, 5]. The metals involved in the antitumor complexes mainly include platinum-based anticancer drugs, such as cisplatin, carboplatin, and oxaliplatin [6, 7]. The physiological distribution and intracellular accumulation of copper complexes differ greatly from platinum complexes, which bring prospects for copper complexes as antitumor drugs to overcome drug resistance [8, 9]
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