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2.
Drug Discov Today ; 29(9): 104100, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39019429

RESUMEN

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.


Asunto(s)
Antineoplásicos , Neoplasias Óseas , Osteosarcoma , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Animales , Relación Estructura-Actividad , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Complejos de Coordinación/química
3.
Inorg Chem ; 63(11): 4925-4938, 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38442008

RESUMEN

Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 µM) and spheroids (IC50 3D: 16.3 ± 3.1 µM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 µM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 µM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 µM, indicating both anticancer and antimetastatic effects.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Niño , Humanos , Adulto Joven , Cobre/farmacología , Ligandos , Osteosarcoma/tratamiento farmacológico
4.
Dalton Trans ; 53(7): 3039-3051, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38111362

RESUMEN

We report the synthesis, characterization and anticancer activity of a new Schiff base (H2L) derived from the condensation of pyridoxamine with pyridoxal and its novel copper(II) and oxidovanadium(IV) complexes: [Cu(HL)Cl] (1), [Cu(LH2)(phen)]Cl2 (2), [Cu(LH2)(amphen)]Cl2 (3), [VIVO(HL)Cl] (4), and [VIVO(LH2)(phen)]Cl2 (5), where phen is 1,10-phenanthroline and amphen is its 5-amino derivative. All compounds were characterized by analytical and spectroscopic techniques, namely FTIR, UV-vis and EPR spectroscopy. Their stability in aqueous media was evaluated, revealing that the presence of the phen co-ligand significantly increases the stability. The ternary Cu(II) complexes (2 and 3) impaired cell viability of osteosarcoma cells (MG-63) (IC50 values of 3.6 ± 0.6 and 7 ± 1.9 µM for 2 and 3), while 1 and the VIVO complexes did not show relevant anticancer activity. Complexes 2 and 3 are also more active than cisplatin (CDDP). Synergistic studies between 2 and sorafenib showed significant synergism on MG-63 cells for the following combinations: 2 (2.0 µM) + sorafenib (10.0 µM) and 2 (2.5 µM) + sorafenib (12.5 µM), whilst the combination of 2 and CDDP did not show synergy. Complex 2 interacts with DNA, inducing significant genotoxic effects on MG-63 cells from 1.0 to 2.5 µM and it increases the ROS levels 880% over basal. Moreover, 2 induces apoptosis at 1.0 and 2.0 µM, while its combination with sorafenib induces apoptosis and necrosis. Finally, compound 2 reduces the cell viability of MG-63 spheroids showing an IC50 value 7-fold lower than that of CDDP (8.5 ± 0.4 µM vs. 65 ± 6 µM). The combination of 2 and sorafenib also showed synergism on spheroids, suggesting that the combination of these drugs improves the anticancer effect against bone cancer cells.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Osteosarcoma , Humanos , Cobre/química , Bases de Schiff/farmacología , Bases de Schiff/química , Antineoplásicos/química , Vitamina B 6/farmacología , Sorafenib , Cisplatino/farmacología , Vitaminas , Complejos de Coordinación/química
5.
Chempluschem ; 88(12): e202300500, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37726222

RESUMEN

Invited for this month's cover are the collaborating groups of Esteban Rodríguez-Arce from the University of Chile and María Contel from The City University of New York Brooklyn College. The cover picture shows "Supergold" a very powerful gender neutral warrior with superpowers who fights against cancer! The warrior's golden armor and sword represent the pharmacological power of the gold atom. Engraved on the shield, the gold-thiosemicarbazone molecules are the warrior's coat of arms. Supergold selectively destroys different cancer cells. More information can be found in the Research Article by Esteban Rodríguez-Arce, María Contel, and co-workers.


Asunto(s)
Oro , Tiosemicarbazonas , Humanos , Oro/farmacología , Tiosemicarbazonas/farmacología , Masculino , Femenino , Antineoplásicos/farmacología
6.
Chem Biol Interact ; 384: 110685, 2023 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-37666443

RESUMEN

Osteosarcoma (OS) is a frequent bone cancer, affecting largely children and young adults. Cisplatin (CDDP) has been efficacious in the treatment of different cancer such us OS but the development of chemoresistance and important side effects leading to therapeutic failure. Novel therapies including copper compounds have shown to be potentially effective as anticancer drugs and one alternative to usually employed platinum compounds. The goal of this work is the evaluation of the in vitro and in vivo antitumoral activity and dilucidate the molecular target of a Cu(II) cationic complex containing a tridentate hydrazone ligand, CuHL for short, H2L=N'-'-(2-hydroxy-3-methoxybenzylidene)thiophene-2-carbohydrazide, against human OS MG-63 cells. Anticancer activity on MG-63 cell line was evaluated in OS monolayer and spheroids. CuHL significantly impaired cell viability in both models (IC50 2D: 2.1 ± 0.3 µM; 3D: 9.1 ± 1.0 µM) (p < 0.001). Additional cell studies demonstrated the copper compound inhibits cell proliferation and conveys cells to apoptosis, determined by flow cytometry. CuHL showed a great genotoxicity, evaluated by comet assay. Proteomic analysis by Orbitrap Mass Spectometry identified 27 differentially expressed proteins: 17 proteins were found overexpressed and 10 underexpressed in MG-63 cells after the CuHL treatment. The response to unfolded protein was the most affected biological process. In addition, in vivo antitumor effects of the compound were evaluated on human OS tumors xenografted in nude mice. CuHL treatment, at a dose of 2 mg/kg i.p., given three times/week for one month, significantly inhibited the progression of OS xenografts and was associated to a reduction in mitotic index and to an increment of tumor necrosis (p < 0.01). Administration of standard-of-care cytotoxic agent CDDP, following the same treatment schedule as CuHL, failed to impair OS growth and progression.

7.
Dalton Trans ; 52(31): 10855-10868, 2023 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-37486008

RESUMEN

The discovery of new coordination compounds with anticancer properties is an active field of research due to the severe side effects of platinum-based compounds currently used in chemotherapy. In the search for new agents for the treatment of cancer, unsymmetrical N2O2-tetradentate ligand (H2L1 and H2L2) and their Ni(II) and Zn(II) asymmetric complexes (NiII-L1-2 and ZnII-L1-2) have been synthesized and fully characterized. 1H NMR studies revealed that the ligands and complexes were stable in mixtures of DMSO : D2O (9 : 1). Complementary UV-Vis studies confirmed that ZnII derivatives also exhibit high stability in mixtures DMSO : buffer (6 : 4) after 24 h. Single-crystal X-ray diffraction studies confirmed the molecular structures of H2L1, H2L2, NiII-L1, and NiII-L2. At the molecular level, complexes were completely planar without significant distortions of the square-planar geometry according to τ4 parameter. Furthermore, the crystalline structures revealed non-classical intermolecular interactions of the C-H⋯O and the Ni⋯Ni type. The ligands and complexes were screened against the human osteosarcoma (MG-63), human colon cancer (HCT-116), breast cancer (MDA-MB-231) cell lines, and non-cancerous cells (L929). H2L1 and H2L2 ligands not caused cytotoxic effects at a concentration of 100 µM, while NiII-L2, ZnII-L1, and ZnII-L2 complexes induce cytotoxic effects in all cell lines. NiII-L2 was a more active complex against MG-63 (3.9 ± 1.5) and HCT-116 (3.4 ± 1.7) cell lines with IC50 values in the low micromolar range. In addition, this compound was 10-, 5-, and 11-fold more potent than cisplatin in MG-63 (39 ± 1.8), HCT-116 (17.2), and MDA-MB-231 (131 ± 18), respectively. Three complexes exhibited great selectivity for tumoral cells with SI values ranging from 1.6 to 7.4.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Humanos , Complejos de Coordinación/química , Ligandos , Dimetilsulfóxido , Difracción de Rayos X , Antineoplásicos/química , Zinc/química , Cristalografía por Rayos X
8.
Chempluschem ; 88(12): e202300115, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37191319

RESUMEN

This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5-nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2 ]± , and/or dimeric species. Neutral [{Au(TSC)}2 ] species were obtained from one of the compounds in dichlomethane/n-hexane solution and characterized by X-ray crystallography revealing a Au-Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki-1) demonstrated its relevant antimigratory and anti-angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis.


Asunto(s)
Antineoplásicos , Tiosemicarbazonas , Oro , Línea Celular Tumoral , Dimetilsulfóxido , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química
9.
Int J Mol Sci ; 24(8)2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37108690

RESUMEN

Breast cancer is the most common cancer in women, with a high incidence estimated to reach 2.3 million by 2030. Triple-Negative Breast Cancer (TNBC) is the greatest invasive class of breast cancer with a poor prognosis, due to the side-effects exerted by the chemotherapy used and the low effectivity of novel treatments. In this sense, copper compounds have shown to be potentially effective as antitumor agents, attracting increasing interest as alternatives to the usually employed platinum-derived drugs. Therefore, the aim of this work is to identify differentially expressed proteins in MDA-MB-231 cells exposed to two copper(II)-hydrazone complexes using label-free quantitative proteomics and functional bioinformatics strategies to identify the molecular mechanisms through which these copper complexes exert their antitumoral effect in TNBC cells. Both copper complexes increased proteins involved in endoplasmic reticulum stress and unfolded protein response, as well as the downregulation of proteins related to DNA replication and repair. One of the most relevant anticancer mechanisms of action found for CuHL1 and CuHL2 was the down-regulation of gain-of-function-mutant p53. Moreover, we found a novel and interesting effect for a copper metallodrug, which was the down-regulation of proteins related to lipid synthesis and metabolism that could lead to a beneficial decrease in lipid levels.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Cobre/farmacología , Línea Celular Tumoral , Proteómica , Espectrometría de Masas , Lípidos/farmacología , Proliferación Celular
10.
Pharmaceutics ; 15(3)2023 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-36986881

RESUMEN

Colorectal cancer is occasionally called colon or rectal cancer, depending on where cancer begins to form, and is the second leading cause of cancer death among both men and women. The platinum-based [PtCl(8-O-quinolinate)(dmso)] (8-QO-Pt) compound has demonstrated encouraging anticancer activity. Three different systems of 8-QO-Pt-encapsulated nanostructured lipid carriers (NLCs) with riboflavin (RFV) were investigated. NLCs of myristyl myristate were synthesized by ultrasonication in the presence of RFV. RFV-decorated nanoparticles displayed a spherical shape and a narrow size dispersion in the range of 144-175 nm mean particle diameter. The 8-QO-Pt-loaded formulations of NLC/RFV with more than 70% encapsulation efficiency showed sustained in vitro release for 24 h. Cytotoxicity, cell uptake, and apoptosis were evaluated in the HT-29 human colorectal adenocarcinoma cell line. The results revealed that 8-QO-Pt-loaded formulations of NLC/RFV showed higher cytotoxicity than the free 8-QO-Pt compound at 5.0 µM. All three systems exhibited different levels of cellular internalization. Moreover, the hemotoxicity assay showed the safety profile of the formulations (less than 3.7%). Taken together, RFV-targeted NLC systems for drug delivery have been investigated for the first time in our study and the results are promising for the future of chemotherapy in colon cancer treatment.

11.
Curr Med Chem ; 30(5): 510-557, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-34789122

RESUMEN

Copper is an essential element for most aerobic organisms, with an important function as a structural and catalytic cofactor, and in consequence, it is implicated in several biological actions. The relevant aspects of chemistry and biochemistry and the importance of copper compounds in medicine give us a comprehensive knowledge of the multifaceted applications of copper in physiology and physiopathology. In this review, we present an outline of the chemistry, and the antitumor properties of copper complexes on breast, colon, and lung cancer cells focus on the role of copper in cancer, the relationship between structure-activity, molecular targets, and the study of the mechanism of action involved in its anticancer activity. This overview is expected to contribute to understanding the design, synthesis, and uses of copper complexes as antitumor agents in the most common cancers.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Humanos , Cobre , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Catálisis , Colon
12.
Int J Mol Sci ; 23(23)2022 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-36499132

RESUMEN

Wild mushrooms have gained great importance for being a source of biologically active compounds. In this work, we evaluate the anticancer and antioxidant activity of a water-soluble crude polysaccharide extract isolated from the fruiting bodies of the Ganoderma aff. australe (GACP). This mushroom was collected in San Mateo (Boyacá, Colombia) and identified based on macroscopic and microscopic characterization. GACP was characterized by UV-Vis spectroscopy, Fourier-transform infrared spectroscopy, high-performance liquid chromatography-diode array detector, and nuclear magnetic resonance. The antiradical and antioxidant activity were evaluated by different methods and its anticancer activity was verified in the osteosarcoma MG-63 human cell line. Chemical and spectroscopic analysis indicated that GACP consisted of ß-D-Glcp-(1→, →3)-ß-D-Glcp-(1→ and α-D-Glcp-(1→ residues. The results of the biological activity showed that GACP exhibited high antioxidant activity in the different methods and models studied. Moreover, the results showed that GACP impaired cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay) and cell proliferation (clonogenic assay) in a dose-response manner on MG-63 cells. The findings of this work promote the use of mushroom-derived compounds as anticancer and antioxidant agents for potential use in the pharmaceutical and food industries.


Asunto(s)
Agaricales , Ganoderma , Humanos , Antioxidantes/química , Agua , Ganoderma/química , Polisacáridos/química , Agaricales/química
13.
J Inorg Biochem ; 236: 111961, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36049258

RESUMEN

Due to the growing prevalence of cancer diseases, new therapeutic options are urgently needed, and drugs based on metal ions other than platinum are alternatives with exciting possibilities. We report the synthesis, characterization and biological effect of mixed-ligand Fe(III)-aminophenolate complexes derived from salicylaldehyde and L-tryptophan with quinoline derivatives as co-ligands, namely 8-hydroxyquinoline (8HQ), [Fe(L)(8HQ)(H2O)] (1) and its 5-cloro derivative (Cl8HQ), [Fe(L)(Cl8HQ)(H2O)] (2). The complex bearing the aminophenolate and lacking the quinoline co-ligand, [Fe(L)(Cl)(H2O)2] (3), was prepared for comparison. The analytical and spectroscopic characterization revealed that 1 and 2 are octahedral Fe(III) complexes with the aminophenolate acting as a dianionic tridentate ligand and 8HQ co-ligands as bidentate chelates. Spectroscopic techniques and molecular docking studies were used to evaluate the ability of these complexes to bind bovine serum albumin (BSA) and calf thymus DNA. Complex 2 [Fe(L)(Cl8HQ)(H2O)] was the one showing higher affinity for both biomolecules. Cell viability was assessed in breast, colorectal and bone human cancer cell lines. 1 and 2 were found to be more active than cisplatin in all cell lines tested. A non-tumoral fibroblast line (L929, mouse non-tumoral fibroblasts) was used to evaluate selectivity. The results evidence that 2 shows much higher selectivity than 1 in all cell lines tested, but particularly in bone cancer cells in which selectivity index (SI) values are 8.0 and 18.8 for 1 and 2, respectively.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cisplatino , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Compuestos Férricos , Humanos , Ligandos , Ratones , Simulación del Acoplamiento Molecular , Oxiquinolina/farmacología , Platino (Metal) , Bases de Schiff/química , Bases de Schiff/farmacología , Albúmina Sérica Bovina/metabolismo , Triptófano
14.
Drug Discov Today ; 27(2): 664-674, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34856395

RESUMEN

Focal Adhesion Kinase (FAK) is a 125-kDa cytoplasmic protein kinase that is implicated in several cellular functions. This protein is an attractive molecular target for cancer therapy because a wide variety of studies have demonstrated associations between the activation or elevated expression of FAK and tumor progression, invasion, and drug resistance in malignant tumors. Here, we review the strategies used to inhibit FAK activity in solid tumors. We also include an overview of the preclinical (in vitro and in vivo) and clinical studies on FAK inhibitors.


Asunto(s)
Neoplasias , Inhibidores de Proteínas Quinasas , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
15.
ChemMedChem ; 17(4): e202100520, 2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-34750978

RESUMEN

The purpose of this work was to screen the anticancer activity and mechanisms of action of Cu(II)-acylhydrazone complex [Cu(HL)(H2 O)](NO3 )⋅H2 O, (CuHL), to find a potential novel agent for breast chemotherapies. Cytotoxicity studies on MCF7 cells demonstrated that CuHL has stronger anticancer properties than cisplatin over breast cancer cell models. Computational simulations showed that CuHL could interact in the minor groove of the DNA dodecamer, inducing a significant genotoxic effect on both cancer cells from 0.5 to 1 µM. In this sense, molecular docking and molecular dynamics simulations showed that the compound could interact with 20S proteasome subunits. Also, cell proteasome experiments using breast cancer cells revealed that the complex can inhibit proteasomal activity. Moreover, CuHL induced apoptosis in breast cancer cells at very low micromolar concentrations (0.5-2.5 µM) and displayed relevant anticancer activity over spheroids derived from MCF7 cells. Ultimately, CuHL diminished the number of mammospheres formed, disturbing their morphology and size.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Complejos de Coordinación/farmacología , Cobre/farmacología , Hidrazonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Cobre/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidrazonas/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales Cultivadas
16.
Eur J Pharm Sci ; 169: 106092, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-34879254

RESUMEN

The main goal of this work was to screen the antiproliferative activity and mechanism of actions of two copper complexes: [Cu(dmp)2(CH3CN)]2+ (1) and [Cu(phen)2(CH3CN)]2+ (2) on 2D and 3D colorectal cancer cells models. Cell viability studies on three colorectal cancer cell lines (HT-29, LS174T, Caco-2) displayed that 1 showed more robust antiproliferative activity than 2 and cisplatin. Intracellular copper content (63.24% and 48.06% for 1 and 2, respectively) can explain the differences in the cytotoxicity assay. ROS production is the primary mechanism of action involved in the antiproliferative activity of 1 showing 4-, 70- and 2.5- fold increased values of ROS level for HT-29, LS174T, Caco-2 cancer cell lines, respectively. This effect takes place along with the depolarization of the mitochondrial membrane at 2 µM. Besides, both complexes increased apoptosis on three cancer cell lines at low micromolar concentrations (0.5-2.5 µM). Moreover, 1 and 2 inhibited NF-κB pathway both in HT-29-NF-kB-hrGFP monolayer (0.5 to 1 µM) and spheroids HT-29 GFP (5 to 10 µM). This inhibitory effect leads to an inactivation of the MMP-9 expression on HT-29 cell line. Altogether, these results showed that 1 exhibits antiproliferative activity on human colorectal cancer cells in the monolayer and the 3D model.


Asunto(s)
Neoplasias Colorrectales , FN-kappa B , Apoptosis , Células CACO-2 , Neoplasias Colorrectales/tratamiento farmacológico , Cobre , Humanos , Especies Reactivas de Oxígeno
17.
Dalton Trans ; 50(34): 11931-11940, 2021 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-34374389

RESUMEN

Improving the binding of metal complexes to DNA to boost cancer cell cytotoxicity requires fine tuning of their structural and chemical properties. Copper has been used as a metal center in compounds containing intercalating ligands due to its ability to catalytically generate reactive oxygen species (ROS), such as hydroxyl radicals (OH˙). We envision the synergy of DNA binding and ROS generation in proximity to target DNA as a powerful chemotherapy treatment. Here, we explore the use of [Cu(2CP-Bz-SMe)]2+ (2CP-Bz-SMe = 1,3-bis(1,10-phenanthrolin-2-yloxy)-N-(4-(methylthio)benzylidene)propan-2-amine) for this purpose by characterizing its cytotoxicity, DNA binding, and ability to affect DNA replication through the polymerase chain reaction - PCR and nuclease assays. We determined the binding (Kb) and Stern-Volmer constants (KSV) for complex-DNA association of 5.8 ± 0.14 × 104 and 1.64 (±0.08), respectively, through absorption titration and competitive fluorescence experiments. These values were superior to those of other Cu-complex intercalators. We hypothesize that the distorted trigonal bipyramidal geometry of [Cu(2CP-Bz-SMe)]2+ allows the phenanthroline fragments to be better accommodated into the DNA double helix. Moreover, the aromaticity of these fragments increases the local hydrophobicity thus increasing the affinity for the hydrophobic domains of DNA. Nuclease assays in the presence of common reducing agents ascorbic acid, nicotinamide adenine dinucleotide, and glutathione showed the effective degradation of DNA due to the in situ generation of OH˙. The [Cu(2CP-Bz-SMe)]2+ complex showed cytotoxicity against the following human cancer cells lines A549, MCF-7, MDA-MB-231 and MG-63 with half maximal inhibitory concentration (IC50) values of 4.62 ± 0.48, 5.20 ± 0.76, 5.70 ± 0.42 and 2.88 ± 0.66 µM, respectively. These low values of IC50, which are promising if compared to that of cisplatin, are ascribed to the synergistic effect of ROS generation with the intercalation ability into the DNA minor grooves and blocking DNA replication. This study introduces new principles for synergizing the chemical and structural properties of intercalation compounds for improved drug-DNA interactions targeting cancer.


Asunto(s)
Cobre , Complejos de Coordinación , Fenantrolinas
18.
Dalton Trans ; 50(28): 9812-9826, 2021 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-34190268

RESUMEN

We report here the synthesis, crystal structure, characterization and anticancer activity of a copper(ii)-hydrazone complex, [Cu(MeBHoVa)(H2O)2](NO3) (for short, CuHL), against human breast cancer cells on monolayer (2D) and spheroids/mammospheres (3D). The solid-state molecular structure of the complex has been determined by X-ray diffraction methods. The conformational space was searched and geometries were optimized both in the gas phase and including solvent effects by computational methods based on DFT. The compound has been characterized in the solid state and in solution by spectroscopic (FTIR, Raman, UV-vis) methods. The results were compared with those obtained for the hydrazone ligand and complemented with DFT calculations. Cell viability assays on MCF7 (IC50(CuHL) = 1.7 ± 0.1 µM, IC50(CDDP) = 42.0 ± 3.2 µM) and MDA-MB-231 (IC50(CuHL) = 1.6 ± 0.1 µM, IC50(CDDP) = 131.0 ± 18 µM) demonstrated that the complex displays higher antitumor activity than cisplatin (CDDP) on 2D and 3D human breast cancer cell models. Molecular docking and molecular dynamics simulations showed that CuHL could interacts with DNA, inducing a significant genotoxic effect on both breast cancer cells from 0.5 to 1 µM. On the other hand, CuHL increases the ROS production and induces cell programmed death on breast cancer cells at very low micromolar concentrations (0.5-1.0 µM). Moreover, the compound decreased the amount of breast CSCs on MCF7 and MDA-MB-231 cells reducing the percentage of CD44+/CD24-/low cells from 0.5 to 1.5 µM. In addition, CuHL overcame CDDP with an IC50 value 65-fold lower against breast multicellular spheroids ((IC50(CuHL) = 2.2 ± 0.3 µM, IC50(CDDP) = 125 ± 4.5 µM)). Finally, CuHL reduced mammosphere formation capacity, hence affecting the size and number of mammospheres and showing that the complex exhibits antitumor properties on monolayer (2D) and spheroids (3D) derived from human breast cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Complejos de Coordinación/farmacología , Cobre/farmacología , Hidrazonas/farmacología , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Cobre/química , Daño del ADN , Femenino , Humanos , Hidrazonas/química , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Mutágenos/química , Mutágenos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos
19.
Int J Pharm ; 605: 120788, 2021 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-34116182

RESUMEN

The three main FDA-approved platinum drugs in chemotherapy such as carboplatin, cisplatin, and oxaliplatin are extensively applied in cancer treatments. Although the clinical applications of platinum-based drugs are extremely effective, their toxicity profile restricts their extensive application. Therefore, recent studies focus on developing new platinum drug formulations, expanding the therapeutic aspect. In this sense, recent advances in the development of novel drug delivery carriers will help with the increase of drug stability and biodisponibility, concomitantly with the reduction of drug efflux and undesirable secondary toxic effects of platinum compounds. The present review describes the state of the art of platinum drugs with their biological effects, pre- and clinical studies, and novel drug delivery nanodevices based on lipids, polymers, and inorganic.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Portadores de Fármacos/uso terapéutico , Humanos , Lípidos , Neoplasias/tratamiento farmacológico , Polímeros/uso terapéutico
20.
Curr Treat Options Oncol ; 22(5): 41, 2021 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-33745006

RESUMEN

OPINION STATEMENT: Osteosarcoma (OS), the most common primary malignant bone tumor, is a vastly aggressive disease in children and adolescents. Although dramatic progress in therapeutic strategies have achieved over the past several decades, the outcome remains poor for most patients with metastatic or recurrent OS. Nowadays, conventional treatment for OS patients is surgery combined with multidrug chemotherapy including doxorubicin, methotrexate, and cisplatin (CDDP). In this sense, cisplatin (CDDP) is one of the most drugs used in the treatment of OS but drug resistance to CDDP appears as a serious problem in the use of this drug in the treatment of OS. Thus, we consider that the understanding the molecular mechanisms and the genes involved that lead to CDDP resistance is essential to developing more effective treatments against OS. In this review, we present an outline of the key role of the long non-coding RNAs (lncRNAs) in CDDP resistance in OS. This overview is expected to contribute to understand the mechanisms of CDDP resistance in OS and the relationship of the expression regulation of several lncRNAs.


Asunto(s)
Neoplasias Óseas/genética , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Osteosarcoma/genética , ARN Largo no Codificante/genética , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Cisplatino/química , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica , Humanos , Osteosarcoma/tratamiento farmacológico
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