RESUMEN
PROPOSE: Tin complexes demonstrate antiproliferative activities in some case higher than cisplatin, with IC50 at the low micromolar range. We have previously showed that the cyclic trinuclear complex of Sn(IV) bearing an aromatic oximehydroxamic acid group [nBu2Sn(L)]3 (L=N,2-dihydroxy-5-[N-hydroxyethanimidoyl]benzamide) (MG85) shows high anti-proliferative activity, induces apoptosis and oxidative stress, and causes destabilization of tubulin microtubules, particularly in colorectal carcinoma cells. Despite the great efficacy towards cancer cells, this complex still shows some cytotoxicity to healthy cells. Targeted delivery of this complex specifically towards cancer cells might foster cancer treatment. METHODS: MG85 complex was encapsulated into liposomal formulation with and without an active targeting moiety and cancer and healthy cells cytotoxicity was evaluated. RESULTS: Encapsulation of MG85 complex in targeting PEGylated liposomes enhanced colorectal carcinoma (HCT116) cancer cell death when compared to free complex, whilst decreasing cytotoxicity in non-tumor cells. Labeling of liposomes with Rhodamine allowed assessing internalization in cells, which showed significant cell uptake after 6 h of incubation. Cetuximab was used as targeting moiety in the PEGylated liposomes that displayed higher internalization rate in HCT116 cells when compared with non-targeted liposomes, which seems to internalize via active binding of Cetuximab to cells. CONCLUSIONS: The proposed formulation open new avenues in the design of innovative transition metal-based vectorization systems that may be further extended to other novel metal complexes towards the improvement of their anti-cancer efficacy, which is usually hampered by solubility issues and/or toxicity to healthy tissues.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Lípidos/química , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos Orgánicos de Estaño/administración & dosificación , Polietilenglicoles/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidad , Transporte Biológico , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cetuximab/administración & dosificación , Cetuximab/química , Cetuximab/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Células HCT116 , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Cinética , Liposomas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Compuestos Orgánicos de Estaño/química , Compuestos Orgánicos de Estaño/metabolismo , Compuestos Orgánicos de Estaño/toxicidadRESUMEN
Reactions between 4'-phenyl-terpyridine (L) and several Cu(II) salts (p-toluenesulfonate, benzoate and o-, m- or p-hydroxybenzoate) led to the formation of [Cu(p-SO3C6H4CH3)L(H2O)2](p-SO3C6H4CH3) (1), [Cu(OCOPh)2L] (2), [Cu(o-OCOC6H4OH)2L] (3), [Cu(m-OCOC6H4OH)2L]4·MeOH (·MeOH) and [Cu(p-OCOC6H4OH)2L]5·2H2O (·2H2O), which were characterized by elemental and TG-DTA analyses, ESI-MS, IR spectroscopy and single crystal X-ray diffraction, as well as by conductivimetry. In all structures the Cu atoms present N3O3 octahedral coordination geometries, which, in 2-5, are highly distorted as a result of the chelating-bidentate mode of one of the carboxylate ligands. Intermolecular π···π stacking interactions could also be found in 2-5 (in the 3.569-3.651 Å range and involving solely the pyridyl rings). Medium-strong hydrogen bond interactions lead to infinite 1D chains (in 1 and 4) and to an infinite 2D network (in 5). Compounds 1 and 4 show high in vitro cytotoxicity towards HCT116 colorectal carcinoma and HepG2 hepatocellular carcinoma cell lines. The antiproliferative potential of compound 1 is due to an increase of the apoptotic process that was confirmed by Hoechst staining, flow cytometry and RT-qPCR. All compounds able to non-covalently intercalate the DNA helix and induce in vitro pDNA double-strand breaks in the absence of H2O2. Concerning compound 1, the hydroxyl radical and singlet oxygen do not appear to be involved in the pDNA cleavage process and the fact that this cleavage also occurs in the absence of molecular oxygen points to a hydrolytic mechanism of cleavage.
RESUMEN
Identification of novel molecules that can selectively inhibit the growth of tumor cells, avoid causing side effects to patients and/or intrinsic or acquired resistance, usually associated with common chemotherapeutic agents, is of utmost importance. Organometallic compounds have gained importance in oncologic chemotherapy, such as organotin(iv) complexes. In this study, we assessed the anti-tumor activity of the cyclic trinuclear organotin(iv) complex with an aromatic oximehydroxamic acid group [nBu2Sn(L)]3(H2L = N,2-dihydroxy-5-[N-hydroxyethanimidoyl]benzamide) - MG85 - and provided further characterization of its biological targets. We have previously shown the high anti-proliferative activity of this complex against human colorectal and hepatocellular carcinoma cell lines and lower cytotoxicity in neonatal non-tumor fibroblasts. MG85 induces tumor cell apoptosis and down-regulation of proteins related to tubulin dynamics (TCTP and COF1). Further characterization included the: (i) evaluation of interference in the cell cycle progression, including the expression of critical genes; (ii) affinity to DNA and the corresponding mode of binding; (iii) genotoxic potential in cells with deficient DNA repair pathways; and (iv) in vivo tumor reduction efficiency using mouse colorectal carcinoma xenografts.
Asunto(s)
Compuestos Orgánicos de Estaño/farmacocinética , Animales , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Aberraciones Cromosómicas , Cristalografía por Rayos X , ADN/metabolismo , Citometría de Flujo , Masculino , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteínas de Neoplasias/metabolismo , Polimerizacion , Espectrofotometría Ultravioleta , Tubulina (Proteína)/metabolismo , Proteína Tumoral Controlada Traslacionalmente 1RESUMEN
Several copper complexes have been assessed as anti-tumor agents against cancer cells. In this work, a copper compound [Cu(H2O){OS(CH3)2}L](NO3)2 incorporating the ligand 4'-phenyl-terpyridine antiproliferative activity against human colorectal, hepatocellular carcinomas and breast adenocarcinoma cell lines was determined, demonstrating high cytotoxicity. The compound is able to induce apoptosis and a slight delay in cancer cell cycle progression, probably by its interaction with DNA and induction of double-strand pDNA cleavage, which is enhanced by oxidative mechanisms. Moreover, proteomic studies indicate that the compound induces alterations in proteins involved in cytoskeleton maintenance, cell cycle progression and apoptosis, corroborating its antiproliferative potential.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Cobre/farmacología , Piridinas/química , Antineoplásicos/química , Apoptosis , Caspasa 3/genética , Complejos de Coordinación/química , Cobre/química , ADN/química , Células Epiteliales/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Citometría de Flujo , Células HCT116 , Células Hep G2 , Humanos , Células MCF-7 , Estrés Oxidativo , Proteómica , Proteínas Proto-Oncogénicas c-bcl-2/genética , Albúmina Sérica/química , Proteína X Asociada a bcl-2/genéticaRESUMEN
BACKGROUND: The discovery of cisplatin's antitumor activity led to a great interest in the potential application of coordination compounds as chemotherapeutic agents. It is essential to identify new compounds that selectively inhibit tumor proliferation, evading secondary effects and resistance associated with chemotherapeutics. METHODS: The in vitro antiproliferative potential of an organotin(IV) compound was evaluated using colorectal and hepatocellular carcinoma, mammary gland adenocarcinoma cell lines, and human fibroblasts. Tumor cell death was evaluated by fluorescence microscopy and flow cytometry for the Sn(IV) compound and also for a Co(II) compound bearing 1,10-phenanthroline-5,6-dione as ligand. Comparative proteomic analysis for both compounds was assessed in the colorectal cancer cell line. RESULTS: The Sn(IV) compound presented a high cytotoxic effect in colorectal and hepatocellular carcinoma cell lines (IC50 of 0.238 ± 0.011 µM, 0.199 ± 0.003 µM, respectively), and a lower cytotoxicity in human fibroblasts. Both compounds induced cell apoptosis and promoted the overexpression of oxidative stress-related enzyme superoxide dismutase [Cu-Zn] (SODC). The Co(II) compound induced a decreased expression of anti-apoptotic proteins (translationally-controlled tumor protein and endoplasmin), and the Sn(IV) compound decreased expression of proteins involved in microtubule stabilization, TCTP, and cofilin-1. CONCLUSIONS: Our data reveals a high in vitro antiproliferative potential against cancer cell lines and a moderate selectivity promoted by the Sn(IV) compound. Proteomic analysis of Sn(IV) and Co(II) compounds in the colorectal cancer cell line allowed an insight to their mechanisms of action, particularly by affecting the expression of proteins typically deregulated in cancer, and also suggesting a promising therapeutic potential for both compounds.