Copper transporter 1 affinity as a delivery strategy to improve the cytotoxic profile of rationally designed copper(II) complexes for cancer treatment

Teles, Ramon Handerson Gomes; Graminha, Angélica E.; Rivera-Cruz, Cosette M.; Nakahata, Douglas Hideki; Formiga, André Luiz Barboza; Corbi, Pedro P.; Figueiredo, Marxa L.; Cominetti, Márcia Regina

doi:10.1016/j.tiv.2020.104922

Cited by 10 publications

(6 citation statements)

References 29 publications

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“…It is an assay used to determine the efficacy of a cytotoxic agent based on cell reproduction. Complex 1 significantly inhibited the colony area and colony intensity in a concentration-dependent manner after 48 h of treatment (Figure A), consistent with the results of MTT, reinforcing the cytotoxic and cytostatic effects of the complex. , …”

Section: Resultssupporting

confidence: 85%

“…Complex 1 significantly inhibited the colony area and colony intensity in a concentration-dependent manner after 48 h of treatment (Figure 5A), consistent with the results of MTT, reinforcing the cytotoxic and cytostatic effects of the complex. 85,86 Morphological analysis of MDA-MB-231 cells treated for 48 h with different concentrations of complex 1 showed a concentration and time-dependent decrease in cell density, the appearance of round cells, and loss of cell adhesion (Figures 5B and S39), all indicative signs of cell death. 87,88 A more refined morphological analysis of the MDA-MB-231 cells was performed by phalloidin staining.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Experimental and Theoretical DFT Study of Cu(I)/N,N-Disubstituted-N′-acylthioureato Anticancer Complexes: Actin Cytoskeleton and Induction of Death by Apoptosis in Triple-Negative Breast Tumor Cells

et al. 2021

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Six complexes with the general formula [Cu(acylthioureato)(PPh3)2] were synthesized and characterized using spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), mass spectrometry, elemental analysis, and X-ray diffraction. Interpretation of the in vitro cytotoxicity data of Cu(I) complexes took into account their stability in cell culture medium. DFT calculations showed that NMR properties, such as the shielding of carbon atoms, are affected by relativistic effects, supported by the ZORA Hamiltonian in the theoretical calculations. Additionally, the calculation of the energies of the frontier molecular orbitals predicted that the structural changes of the acylthiourea ligands did not cause marked changes in the reactivity descriptors. All complexes were cytotoxic to the evaluated tumor cell lines [MDA-MB-231 (triple-negative breast cancer, TNBC), MCF-7 (breast cancer), and A549 (lung cancer)]. In the MDA-MB-231 cell line, complex 1 significantly altered the cytoskeleton of the cells, reducing the density and promoting the condensation of F-actin filaments. In addition, the compound caused an increase in the percentage of cells in the fragmented DNA region (sub-G0) and induced cell death via the apoptotic pathway starting at the IC50 concentration. Taken together, the results show that complex 1 has cytotoxic and apoptotic effects on TNBC cells, which is a cell line originating from an aggressive, difficult-to-treat breast cancer.

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Section: Resultssupporting

confidence: 85%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Experimental and Theoretical DFT Study of Cu(I)/N,N-Disubstituted-N′-acylthioureato Anticancer Complexes: Actin Cytoskeleton and Induction of Death by Apoptosis in Triple-Negative Breast Tumor Cells

et al. 2021

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“…Moreover, copper-containing complexes or materials also behave as bearers of high thermal and electrical conductivity, or catalytic and sensory features. As examples, the following papers could be mentioned to show the current strives on the design of copper(II) complexes showing some of the above mentioned properties, mainly the antiproliferative one [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. To date, one of the most intensively studied groups of copper(II) complexes in terms of their possible clinical use as anticancer agents is the copper(II) complexes called Casiopeínas ® , whose composition can be expressed by the formulas [Cu( N – N )( N – O )] + and/or [Cu( N – N )( O – O )] + , where ( N – N ) represents an aromatic heterocyclic diimine, such as 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), ( N – O ) and ( O – O ) stands for an amino acid, and acetylacetone, respectively [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

Vančo

Trávníček

Hošek

et al. 2021

IJMS

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A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b']dipyran-4-one, (pomiferin) and bpy = 2,2'-bipyridine, dimebpy = 4,4ʹ-dimethyl-2,2ʹ-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2',3'-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2–13.0 μM for the best performing complexes 3 and 5. All the complexes 1–5 showed the best activity against the A2780R cells (IC50 = 2.2–6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.

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“…Finally, we did not focus on the transport mechanisms of the Cu 2+ complexes in this study. Previous studies on the cytotoxicity of several copper(II) complexes for cancer treatment have demonstrated that copper transporter 1 plays critical roles in cancer cell uptake of copper(II) complexes [43]. Therefore, copper transporter 1 may also contribute to the transportation of 64 Cu 2+ -Tren and 64 Cu 2+ -Dien.…”

Section: Discussionmentioning

confidence: 99%

<sup>64</sup>Cu<sup>2+ </sup>Complexes of Tripodal Amine Ligands on In Vivo Tumor and Liver Uptake and Intracellular Cu Distribution in the Extrahepatic Bile Duct Carcinoma Cell Line TFK-1: A Basic Comparative Study

Shinada,

Takahashi,

Igarashi

et al. 2024

Preprint

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Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. 64Cu2+ is an anticancer radiopharmaceuticals targeting the copper requirement of cancer cells. However, intravenously injected 64Cu2+ ions primarily accumulate in the liver. Ligand complexation of 64Cu2+ would be a promising method for increasing tumor delivery by reducing liver uptake. Herein, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose 64Cu2+ ions and compared their in vivo tumor and liver uptake using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis for these compounds. 64Cu2+-Tren and 64Cu2+-Dien showed higher tumor uptake than 64Cu2+-TPMA and 64Cu2+ ions in TFK-1 tumors. Among the three 64Cu2+ complexes and 64Cu2+ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake and nuclear delivery was the highest for 64Cu2+-Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three 64Cu2+ complexes of tripodal amine ligands and 64Cu2+ ions. These results provide useful information for the future development of anticancer 64Cu radiopharmaceuticals.

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Copper transporter 1 affinity as a delivery strategy to improve the cytotoxic profile of rationally designed copper(II) complexes for cancer treatment

Cited by 10 publications

References 29 publications

Experimental and Theoretical DFT Study of Cu(I)/N,N-Disubstituted-N′-acylthioureato Anticancer Complexes: Actin Cytoskeleton and Induction of Death by Apoptosis in Triple-Negative Breast Tumor Cells

Experimental and Theoretical DFT Study of Cu(I)/N,N-Disubstituted-N′-acylthioureato Anticancer Complexes: Actin Cytoskeleton and Induction of Death by Apoptosis in Triple-Negative Breast Tumor Cells

Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

<sup>64</sup>Cu<sup>2+ </sup>Complexes of Tripodal Amine Ligands on In Vivo Tumor and Liver Uptake and Intracellular Cu Distribution in the Extrahepatic Bile Duct Carcinoma Cell Line TFK-1: A Basic Comparative Study

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