Metalofármacos de cobre, platino y vanadio : Potencial actividad antitumoral y estudios de mecanismos de acción en modelos in vitro e in vivo

Los objetivos de la presente tesis doctoral son: 1- Realizar un screening de la actividad antitumoral en líneas celulares humanas de hueso y colón de fenotipo normal y tumoral de diversos metalocompuestos con diversos ligandos como por ejemplo flavonoides (crisina y silibinina), ligandos de interés biológico que presentan grupos funcionales aptos para la coordinación con metales como por ejemplo quinolinas o compuestos con varios átomos coordinantes como el oxodiacetato, diversos heterociclos como 2,2´ bipiridina y la o-fenantrolina, y finalmente, compuestos de naturaleza inorgánica como los polioxometalatos. 2- Evaluar los efectos de los metalofármacos y de sus precursores sobre la cito- y genotoxicidad. 3- Investigar los posibles mecanismos de acción de los metalocompuestos bioactivos involucrados en sus propiedades antitumorales en esas líneas celulares. 4- Investigar las propiedades antitumorales de aquellos compuestos seleccionados por su mayor actividad in vitro, en un modelo de ratones N:NIH(S) Fox1nu inoculados con células de osteosarcoma humano MG-63, para evaluar su capacidad antitumoral en un sistema in vivo.Facultad de Ciencias Exacta

Spectroscopic characterization of an Oxovanadium(IV) complex of Oxodiacetic acid and 2,2’-Bipyridine : Bioactivity on Osteoblast-like cells in culture

The oxovanadium(IV) complex of oxodiacetic acid (H2ODA) and 2,2’-bipyridine (bipy) of stoichiometry [VO(ODA)(bipy)]⋅H2O, was thoroughly characterized by infrared, Raman and electronic spectroscopies. The biological activity of the complex on the cell proliferation was tested on osteoblast-like cells (MC3T3E1 osteoblastic mouse calvaria-derived cells and UMR106 rat osteosarcoma-derived cells) in culture. The complex caused inhibition of cellular proliferation in both osteoblast-like cells in culture, but its action was statistically stronger in the tumoral cells. This effect was specially marked with increasing concentrations of the complex. Based on these preliminary biological results, [VO(ODA)(bipy)]⋅H2O can be considered as a good candidate to be further investigated in relation to cancer treatment.El complejo de oxovanadio(IV) del ácido oxodiacético (H2ODA) y 2,2’-dipiridina (bipy) de estequiometría [VO(ODA)(bipy)]⋅H2O, fue caracterizado detalladamente por espectroscopia infrarroja, Raman y electrónica. La actividad biológica del complejo sobre la proliferación celular fue ensayada sobre células osteoblásticas de fenotipo normal (MC3T3-E1) y tumorales (UMR106) en cultivo. El complejo fue más deletéreo sobre los osteoblastos tumorales que sobre los de fenotipo normal, siendo este efecto más marcado con el aumento de la concentración del mismo. Los resultados de estos estudios biológicos permiten considerar al [VO(ODA)(bipy)]⋅H2O como un buen candidato para futuros estudios en relación a los tratamientos antitumorales.Facultad de Ciencias ExactasCentro de Química Inorgánic

Vanadium, Ruthenium and Copper Compounds : A New Class of Nonplatinum Metallodrugs with Anticancer Activity

Cancer is a group of diseases involving abnormal cell growth. The cells grow uncontrollably with the potential to invade and spread to other parts of the body. This disease is one of the principal death causes in the world, thus becoming a significant topic of scientific research. On the other hand, transition metals play a fundamental role in different living systems. In particular, Metallodrugs represent new and powerful tools for diverse therapeutic applications. To date, various metallodrugs display interesting biological activities for chemotherapy. In this field, cisplatin was the first inorganic compound with high relevance in cancer treatment. This compound was a leader agent in clinical use. Toxicity and resistance problems trigger the development of other platinum drugs with better clinical perspective and also raise the scientific interest for the putative antitumor properties of V, Ru and Cu compounds. Several scientific articles show that complexes of these metals are the new metal-based drugs used in the treatment of several cancers, such us, lung, colon, breast, bladder, etc. In this review we recapitulate current information and new advances on antitumor in vitro effects of several organic and inorganic compounds derived from copper, ruthenium and vanadium. These metal derived compounds targeting DNA or cell proteins involved in cell signaling pathways related to cancer. The mechanisms of cell death of these metallodrugs have also been comprehensibly reviewed. The knowledge of these mechanisms of death and the relationship between chemical structure and biological activity may be useful for the design of new metal-based drugs with promising pharmacologic applications as anticancer agents.Centro de Química Inorgánic

Cytotoxicity action of an oxidovanadium(IV)-DPPZ complex on MG-63 human osteosarcoma cell line

The cytotoxicity activity of the recently reported [VO(H2O)2(SO4)dppz]·2H2O complex (dppz = dipyrido[3,2-a:2',3'- c]phenazine) on MG-63 human osteosarcoma cell line was investigated. It was found that it caused a concentration related inhibitory effect in the concentration range between 5 and 25 µM and diminished the cell viability ca. 40% in the range from 25 to 100 µM, without dose/response effects in this range. These biological effects are, in general, similar to those previously reported for the related [VO(ODA)dppz]·3H2O (ODA = dianion of oxodiacetic acid) and [VO(ODA)(phen)]·1.5H2O (phen = o- phenanthroline) complexes. The importance of the presence of DNAintercalating ligands in these complexes is emphasized.Facultad de Ciencias ExactasCentro de Química Inorgánic

Modified bacterial cellulose scaffolds for localized doxorubicin release in human colorectal HT-29 cells

Bacterial cellulose (BC) films modified by the in situ method with the addition of alginate (Alg) during the microbial cultivation of Gluconacetobacter hansenii under static conditions increased the loading of doxorubicin by at least three times. Biophysical analysis of BC-Alg films by scanning electron microscopy, thermogravimetry, X-ray diffraction and FTIR showed a highly homogeneous interpenetrated network scaffold without changes in the BC crystalline structure but with an increased amorphous phase. The main molecular interactions determined by FTIR between both biopolymers clearly suggest high compatibility. These results indicate that alginate plays a key role in the biophysical properties of the hybrid BC matrix. BC-Alg scaffold analysis by nitrogen adsorption isotherms revealed by the Brunauer?Emmett?Teller (BET) method an increase in surface area of about 84% and in pore volume of more than 200%. The Barrett?Joyner?Halenda (BJH) model also showed an increase of about 25% in the pore size compared to the BC film.Loading BC-Alg scaffolds with different amounts of doxorubicin decreased the cell viability of HT-29 human colorectal adenocarcinoma cell line compared to the free Dox from around 95?53% after 24 h and from 63% to 37% after 48 h. Dox kinetic release from the BC-Alg nanocomposite displayed hyperbolic curves related to the different amounts of drug payload and was stable for at least 14 days. The results of the BC-Alg nanocomposites show a promissory potential for anticancer therapies of solid tumors.Centro de Investigación y Desarrollo en Fermentaciones IndustrialesCentro de Química Inorgánic

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.Centro de Química Inorgánic

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.Centro de Química Inorgánic

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.Centro de Química Inorgánic

Decoding the anticancer activity of VO-clioquinol compound: the mechanism of action and cell death pathways in human osteosarcoma cells

Vanadium compounds were studied in recent years by considering them as a representative of a new class of non-platinum metal anticancer drugs. However, a few challenges still remain in the discovery of new molecular targets of these new metallodrugs. Studies on cell signaling pathways related to vanadium compounds have scarcely been reported and so far this information is highly critical for identifying novel targets that play a key role in the antitumor actions of vanadium complexes. This research deals with the alterations in the intracellular signaling pathways promoted by an oxovanadium(IV) complex with the clioquinol (5-chloro-7-iodo-8-quinolinol), VO(CQ)2, on a human osteosarcoma cell line (MG-63). Herein are reported, for the first time, the antitumor properties of VO(CQ)2 and the relative abundance of 224 proteins (which are involved in most of the common intracellular pathways) to identify novel targets of the studied complex. Besides, full-length human recombinant AKT1 kinase was produced by using an IVTT system to evaluate the variation of relative tyrosin-phosphorylation levels caused by this compound. The results of the differential protein expression levels reveal several up-regulated proteins such as CASP3, CASP6, CASP7, CASP10, CASP11, Bcl-x, DAPK and down-regulated ones, such as PKB/AKT, DIABLO, among others. Moreover, cell signaling pathways involved in several altered pathways related to the PKC and AP2 family have been identified in both treatments (2.5 and 10 μM) suggesting the crucial antitumoral role of VO(CQ)2. Finally, it has been demonstrated that this compound (10 μM, 6 h) triggers a decrease of 2-fold in in situ AKT1 expression.Puede accederse a los datos primarios de este trabajo haciendo clic en "Documentos relacionados".Facultad de Ciencias ExactasCentro de Química Inorgánic

In silico and in vitro analysis of FAK/MMP signaling axis inhibition by VO-clioquinol in 2D and 3D human osteosarcoma cancer cells

The study of novel mechanisms of action of vanadium compounds is critical to elucidating the role and importance of these kinds of compounds as antitumor and antimetastatic agents. This work deals with in silico and in vitro studies of one clioquinol oxidovanadium(IV) complex [VO(clioquinol)2], VO(CQ)2, and its regulation of FAK. In particular, we focus on elucidating the relationship of the FAK inhibition, MMP activity and antimetastatic effects of the complex in human bone cancer cells.Centro de Química Inorgánic