RESUMEN
Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.
Asunto(s)
Apoptosis , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Leucemia , Linfoma , Mitocondrias , Proteína Inhibidora de la Apoptosis Ligada a X , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Humanos , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Leucemia/metabolismo , Leucemia/tratamiento farmacológico , Leucemia/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Antineoplásicos/farmacologíaRESUMEN
Ruthenium(II) complexes with N-heterocyclic carbene (NHC) ligands have recently attracted attention as novel chemotherapeutic agents. The complex HB324 was intensively studied as an apoptosis-inducing compound in resistant cell lines. HB324 induced apoptosis via mitochondrial pathways. Of particular interest is the upregulation of the Harakiri resistance protein, which inhibits the anti-apoptotic and death repressor proteins Bcl-2 (B-cell lymphoma 2) and BCL-xL (B-cell lymphoma-extra large). Moreover, HB324 showed synergistic activity with various established anticancer drugs and overcame resistance in several cell lines, such as neuroblastoma cells. In conclusion, HB324 showed promising potential as a novel anticancer agent in vitro, suggesting further investigations on this and other preclinical ruthenium drug candidates.
Asunto(s)
Antineoplásicos , Neuroblastoma , Rutenio , Humanos , Cisplatino/farmacología , Rutenio/farmacología , Regulación hacia Arriba , Apoptosis , Antineoplásicos/farmacología , Neuroblastoma/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted α-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 µmole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6/BeKa) with p-glycoprotein expression.
Asunto(s)
Citostáticos , Leucemia , Linfoma , Apoptosis , Caspasa 3 , Carmin de Índigo , Leucemia/tratamiento farmacológico , Hojas de la PlantaRESUMEN
BACKGROUND: Redox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable. METHODS: Bio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5'-CH2O-TDS substituent. Four of these metal-containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1-transgenic splenocytes. RESULTS: The MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA-evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA-triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (∆ΨM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis. CONCLUSIONS: Redox-active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/patología , Mitocondrias/metabolismo , Nucleósidos/farmacología , Oncogenes , Compuestos Organometálicos/farmacología , Proteínas Proto-Oncogénicas/genética , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Caspasa 3/metabolismo , Línea Celular Tumoral , Metabolismo Energético/efectos de los fármacos , Homeostasis/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Necrosis , Nucleósidos/química , Compuestos Organometálicos/química , Factores de Riesgo , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Gold complexes could be promising for tumor therapy because of their cytotoxic and cytostatic properties. We present novel gold(I) complexes and clarify whether they also show antitumor activity by studying apoptosis induction in different tumor cell lines in vitro, comparing the compounds on resistant cells and analyzing the mechanism of action. We particularly highlight one gold complex that shows cytostatic and cytotoxic effects on leukemia and lymphoma cells already in the nanomolar range, induces apoptosis via the intrinsic signaling pathway, and plays a role in the production of reactive oxygen species. Furthermore, not only did we demonstrate a large number of resistance overcomes on resistant cell lines, but some of these cell lines were significantly more sensitive to the new gold compound. Our results show promising properties for the gold compound as anti-tumor drug and suggest that it can subvert resistance mechanisms and thus targets resistant cells for killing.
Asunto(s)
Antineoplásicos , Citostáticos , Leucemia , Linfoma , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Citostáticos/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Oro/farmacología , Leucemia/patología , Linfoma/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
Tris-(8-quinolinolato)gallium(III) (KP46, AP-002) is an orally administered investigational anticancer and bone-protective drug currently being evaluated in patients with advanced solid tumors with bone involvement. Despite the clinical efficacy of other gallium compounds in non-Hodgkin's lymphoma, effects of KP46 in hematological tumor settings have not been studied systematically before. We report here intriguing activities in various human cell lines, including such with multidrug resistance (MDR): In Nalm-6 lymphoblastic leukemia cell sublines, KP46 was capable of overcoming P-gp-related as well as P-gp-unrelated MDR. Apoptosis induction by KP46 was unaffected by bcl2-mediated vincristine-induced MDR in a BJAB lymphoma cell subline and even enhanced in a K562 leukemia subline with daunorubicin-induced MDR, which could be re-sensitized to daunorubicin by KP46. As the latter resistance is associated with lowered Harakiri (HRK) protein levels, a modulating effect of KP46 on HRK expression is suggested. This is consistent with the significant high upregulation of HRK on RNA and protein levels observed in KP46-treated parental BJAB cells according to qPCR and Western blot analysis, respectively. Furthermore, KP46 significantly reduces the protein level of X-linked inhibitor of apoptosis (XIAP) in BJAB cells, the most potent known inhibitor of apoptosis. Overall, these results indicate both a higher potential of HRK and XIAP as cellular targets for cancer therapy and a broader therapeutic potential of KP46 than hitherto envisaged.
Asunto(s)
Galio , Leucemia , Linfoma , Compuestos Organometálicos , Humanos , Regulación hacia Abajo , Regulación hacia Arriba , Galio/farmacología , Compuestos Organometálicos/farmacología , Resistencia a Múltiples Medicamentos , Apoptosis , Leucemia/tratamiento farmacológico , Daunorrubicina/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/genéticaRESUMEN
Hexacarbonyl[1,3-dimethoxy-5-((4'-methoxyphenyl)ethynyl)benzene]dicobalt (NAHO27), an organometallic analogue of combretastatin A-4, has been synthesized and its activity against lymphoma, leukemia, breast cancer and melanoma cells has been investigated. It was shown that NAHO27 specifically induces apoptosis in BJAB lymphoma and Nalm-6 leukemia cells at low micromolar concentration and does not affect normal leukocytes in vitro. It also proved to be active against vincristine and daunorubicin resistant leukemia cell lines with p-glycoprotein-caused multidrug resistance and showed a pronounced (550%) synergistic effect when co-applied with vincristine at very low concentrations. Mechanistic investigations revealed NAHO27 to induce apoptosis via the mitochondrial (intrinsic) pathway as reflected by the processing of caspases 3 and 9, the involvement of Bcl-2 and smac/DIABLO, and the reduction of mitochondrial membrane potential. Gene expression analysis and protein expression analysis via western blot showed an upregulation of the proapoptotic protein harakiri by 9%.
RESUMEN
Colchicine, the main active alkaloid from Colchicum autumnale L., is a potent tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising biological activities. In particular, the previously undescribed colchicinoid PT-100, a B-ring contracted 6-exo-methylene colchicinoid, exhibits extraordinarily high antiproliferative and apoptosis-inducing effects on various types of cancer cell lines like acute lymphoblastic leukemia (Nalm6), acute myeloid leukemia (HL-60), Burkitt-like lymphoma (BJAB), human melanoma (MelHO), and human breast adenocarcinoma (MCF7) cells at low nanomolar concentrations. Apoptosis induction proved to be especially high in multidrug-resistant Nalm6-derived cancer cell lines, while healthy human leukocytes and hepatocytes were not affected by the concentration range studied. Furthermore, caspase-independent initiation of apoptosis via an intrinsic pathway was observed. PT-100 also shows strong synergistic effects in combination with vincristine on BJAB and Nalm6 cells. Cocrystallization of PT-100 with tubulin dimers revealed its (noncovalent) binding to the colchicine-binding site of ß-tubulin at the interface to the α-subunit. A pronounced effect of PT-100 on the cytoskeleton morphology was shown by fluorescence microscopy. While the reactivity of PT-100 as a weak Michael acceptor toward thiols was chemically proven, it remains unclear whether this contributes to the remarkable biological properties of this unusual colchicinoid.
RESUMEN
PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Leucemia/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Apoptosis , Proliferación Celular , Cisplatino/farmacología , Humanos , Leucemia/metabolismo , Leucemia/patología , Ligandos , Mitocondrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Células Tumorales CultivadasRESUMEN
The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC50 values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 µM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Oro/química , Triazoles/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/química , Daunorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , HumanosRESUMEN
Screening of a library of structurally unusual osmacyclic complexes for their antiproliferate properties in HeLa cells led to the discovery of a highly cytotoxic eta2-allene osmacycle. In this remarkably stable complex, osmium constitutes part of a metallacycle through the formation of a sigma-bond to a carbon in combination with coordination to an allene moiety. The osmacycle strongly induces apoptosis in Burkitt-like lymphoma cells at submicromolar concentrations. The reduction of the mitochondrial membrane potential, the induction of DNA fragmentation, and the activation of caspases-9 and -3 reveal that programmed cell death occurs through the intrinsic mitochondrial pathway. From the lipophilic and cationic nature of the osmacycle, in addition to a low oxidation potential (E1/2=+0.27 V vs. Fc/Fc+, Fc=ferrocene) it is proposed that mitochondria are the cellular target where oxidative decomposition initiates apoptosis.
Asunto(s)
Alcadienos/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Alcadienos/farmacología , Antineoplásicos/síntesis química , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Caspasas/metabolismo , Línea Celular Tumoral , Fragmentación del ADN , Humanos , Mitocondrias/metabolismo , Compuestos OrganometálicosRESUMEN
PURPOSE: We report on our preclinical findings of a simple salicylic diamine compound (THG 1213) which has yielded exceptional results as a potential chemotherapeutic drug. THG 1213 is an easy to synthesize chiral and metal-free salan compound. METHODS: THG 1213 was tested on several leukemia, lymphoma and solid tumor cell lines in vitro. The effects have been studied by LDH release essay, FACS flow cytometry, photometric cell count, immunoblotting, and NMR spectroscopy. RESULTS: THG 1213 selectively inhibits proliferation and induces apoptosis in leukemia, lymphoma and solid tumor cell lines. Necrosis or effects on healthy leucocytes could not be detected. Apoptosis is induced via the intrinsic and extrinsic pathways. The salan THG 1213 overcomes multidrug resistance in tumor cells and acts synergistically with vincristine and daunorubicin. CONCLUSIONS: THG 1213 displays remarkable antitumor properties. In particular, the lack of metallic components of THG 1213 could prove to be beneficial in future clinical trials, as metal-containing drugs are known to show severe side effects.
Asunto(s)
Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Fenilendiaminas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daunorrubicina/administración & dosificación , Daunorrubicina/farmacología , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Leucemia/patología , Linfoma/patología , Neoplasias/tratamiento farmacológico , Fenilendiaminas/administración & dosificación , Salicilatos/administración & dosificación , Salicilatos/farmacología , Vincristina/administración & dosificación , Vincristina/farmacologíaRESUMEN
Naphthalimide-based N-heterocyclic carbene (NHC) complexes of the type [(1,5-cyclooctadiene)(NHC)RhCl)] (4 a-c), [(p-cymene)(NHC)RuCl2 )] (5 a-c), and [(NHC)CuBr] (6 a-c) were synthesized and investigated as antiproliferative agents that target DNA. The cytotoxic effects were largely driven by the naphthalimide structure, which is a DNA-intercalating moiety. Regarding the metal center, the highest activities were observed with the rhodium complexes, and cytotoxic activity was significantly lower for the ruthenium derivatives. The stable coordination of the NHC ligands of selected complexes 4 b and 5 b in solution was confirmed, and their DNA binding properties were studied by UV/Vis spectroscopy, mass spectrometry, and circular dichroism. Stable intercalative binding into the DNA for all selected naphthalimide-based complexes is indicated by high DNA binding constants. Particularly efficient binding was observed in the case of the rhodium complex 4 b. More detailed biological studies on 4 b showed promising activities against multidrug-resistant Nalm-6 cells and confirmed an important role for mitochondrial pathways in 4 b-induced apoptosis.
Asunto(s)
Complejos de Coordinación/química , ADN/química , Sustancias Intercalantes/química , Metano/análogos & derivados , Naftalimidas/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dicroismo Circular , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Cristalografía por Rayos X , Cimenos , ADN/metabolismo , Estabilidad de Medicamentos , Células HT29 , Humanos , Sustancias Intercalantes/síntesis química , Sustancias Intercalantes/toxicidad , Ligandos , Células MCF-7 , Metano/química , Conformación Molecular , Monoterpenos/química , Rodio/química , Rutenio/química , Espectrofotometría UltravioletaRESUMEN
Starting from commercially available phloracetophenone (= 1-(2,4,6-trihydroxyphenyl)ethanone), we synthesized demethylxanthohumol (4), a derivative of xanthohumol, devoid of 6'-O-methyl group. Both are prenylchalcones derived from hops (Humulus lupulus). The synthesis was accomplished by an aldol condensation between MOM-protected acetophenone 2 and MOM-protected benzaldehyde 3. The resulting demethylxanthohumol (4) displayed antiproliferative properties. Demethylxanthohumol (4) induced also apoptosis via the mitochondrial pathway in BJAB cells (Burkitt lymphoma cell line) and in primary lymphoblasts of childhood acute lymphoblastic leukemia (ALL).
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Humulus/química , Propiofenonas/química , Propiofenonas/farmacología , Línea Celular Tumoral , Humanos , Estructura MolecularRESUMEN
Gold(i) complexes with phosphane and thiotetrazolate ligands were prepared and investigated as a new type of bioactive gold metallodrugs. The complexes triggered very efficient inhibition of the enzyme thioredoxin reductase (TrxR), which is an important molecular target for gold species. Strong cytotoxic effects were observed in MDA-MB-231 breast adenocarcinoma and HT-29 colon carcinoma cells, and the complexes also caused strong effects in vincristine resistant Nalm-6 leukemia cells. Cellular uptake studies showed elevated cellular gold levels for complexes containing a triphenylphosphane ligand, whereas trifurylphosphane analogues accumulated at significantly lower cellular concentrations.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Inhibidores Enzimáticos/química , Oro/química , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/toxicidad , Cristalografía por Rayos X , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/toxicidad , Células HT29 , Humanos , Conformación Molecular , Fosfinas/química , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
In this study, we investigated the anticancer properties of methoxy-substituted nickel(II)(salophene) derivatives. We demonstrated that the most active complex [NiII(3-OMe-salophene)] is not necrotic in Burkitt-like lymphoma cells (BJAB) and human B-cell precursor cells (Nalm-6). [NiII(3-OMe-salophene)] inhibited proliferation and induced apoptosis in a concentration dependent manner, giving evidence for the involvement of CD95 receptor-mediated, extrinsic pathway. Furthermore, [NiII(3-OMe-salophene)] overcame vincristine drug resistance in BJAB and Nalm-6 cells.
Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Proteína de Dominio de Muerte Asociada a Fas/biosíntesis , Humanos , Péptidos y Proteínas de Señalización Intracelular , Espectroscopía de Resonancia Magnética , Proteínas Mitocondriales/biosíntesis , Necrosis , Transducción de Señal , Relación Estructura-Actividad , Vincristina/farmacología , Receptor fas/fisiologíaRESUMEN
A strategy for combinatorial parallel coordination chemistry is introduced that provides access to libraries of tris-heteroleptic ruthenium complexes in an economical fashion. Using this method, a library of 560 constitutionally unique, monocationic ruthenium complexes was synthesized, followed by a screening for anticancer activity and resulting in the identification of three hits with promising cytotoxic properties in HeLa cancer cells. A subsequent structure-activity relationship led to the discovery of the surprisingly simple anticancer complex [Ru(tBu(2)bpy)(2)(phox)]PF(6) (complex 1), with tBu(2)bpy = 4,4'-di-tert-buty-2,2'-bipyridine and Hphox = 2-(2'-hydroxyphenyl)oxazoline, displaying an LC(50) value in HeLa cells of 1.3 microM and 0.3 microM after incubation for 24 and 72 h, respectively. Complex 1 also shows remarkable antiproliferative and apoptotic properties at submicromolar concentrations in more clinically relevant Burkitt-like lymphoma cells. A reduction of the mitochondrial membrane potential by 1 indicates the involvement of the intrinsic pathway of programmed cell death. Further investigations reveal that 1 requires caspase-3 for the induction of apoptosis but is insensitive to the proapoptotic and antiapoptotic proteins Smac and Bcl-2, respectively.
Asunto(s)
Antineoplásicos/química , Apoptosis , Complejos de Coordinación/química , Compuestos Organometálicos/química , Rutenio/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Técnicas Químicas Combinatorias , Complejos de Coordinación/toxicidad , Evaluación Preclínica de Medicamentos , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Compuestos Organometálicos/toxicidad , Relación Estructura-ActividadRESUMEN
In this study, we investigate the anticancer properties of an inert half-sandwich metal complex scaffold. UV melting experiments with duplex DNA and (1)H-NMR experiments with 9-ethylguanine reveal that the apoptotic ruthenium complex DW12 does not interact with DNA. On the other hand, diminishing the kinase inhibition properties of DW12 by methylating the maleimide nitrogen (DW12-Me) abolishes the anticancer activity. Furthermore, the incorporation of a fluorine into the pyridine moiety (NP309) improves the IC(50) value for glycogen synthase kinase 3 (GSK-3) and at the same time the cytotoxicity, implying that the anticancer activity correlates with the inhibition of GSK-3 and maybe other not yet identified kinases. We demonstrate in Burkitt-like lymphoma (BJAB) cells that NP309 is not necrotic but induces apoptosis and that this apoptosis is mediated by a loss of the mitochondrial membrane potential, caspase-9 processing, and is partly dependent on Bcl-2 expression. In addition, NP309 efficiently induces apoptosis in vincristine- and cytarabine-resistant human B-cell precursor cell lines.
Asunto(s)
Antineoplásicos/química , Complejos de Coordinación/química , Rutenio/química , Antineoplásicos/toxicidad , Apoptosis , Caspasa 9/metabolismo , Línea Celular , Complejos de Coordinación/toxicidad , Glucógeno Sintasa Quinasa 3/metabolismo , Células HCT116 , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
The identification of effective cancer preventive compounds from hops has become an important issue in public health-related research. We compared the antiproliferative and apoptosis-inducing effects of side chain variants of prenylflavanones, e. g., 8-prenylnaringenin (7) and 8-geranylnaringenin (10), which have been identified in hops (Humulus lupulus), and their synthetic variations 8-furanmethylnaringenin (8) and 8-cinnamylnaringenin (9). These were accessible by a Mitsunobu reaction and Claisen rearrangement. Flavanones 9 and 10 showed cytotoxic and apoptotic activities. Apoptosis was induced in a mitochondrial dependent manner. 8-Cinnamylnaringenin (9) displayed noticeably improved apoptotic effects when compared to 8-prenylnaringenin. The potential of 8-prenylnaringenin (7) is shown in an ex vivo experiment on a multi-drug resistant leukaemia blast.