RESUMO
Arsenoplatin-1 (AP-1) is a dual-action anticancer metallodrug with a promising pharmacological profile that features the simultaneous presence of a cisplatin-like center and an arsenite center. We investigated its interactions with proteins through a joint experimental and theoretical approach. The reactivity of AP-1 with a variety of proteins, including carbonic anhydrase (CA), superoxide dismutase (SOD), myoglobin (Mb), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and human serum albumin (HSA), was analyzed by means of electrospray ionization mass spectrometry (ESI MS) measurements. In accordance with previous observations, ESI MS experiments revealed that the obtained metallodrug-protein adducts originated from the binding of the [(AP-1)-Cl]+ fragment to accessible protein residues. Remarkably, in two cases, i.e., Mb and GAPDH, the formation of a bound metallic fragment that lacked the arsenic center was highlighted. The reactions of AP-1 with various nucleophiles side chains of neutral histidine, methionine, cysteine, and selenocysteine, in neutral form as well as cysteine and selenocysteine in anionic form, were subsequently analyzed through a computational approach. We found that the aquation of AP-1 is energetically disfavored, with a reaction free energy of +19.2 kcal/mol demonstrating that AP-1 presumably attacks its biological targets through the exchange of the chloride ligand. The theoretical analysis of thermodynamics and kinetics for the ligand-exchange processes of AP-1 with His, Met, Cys, Sec, Cys-, and Sec- side chain models unveils that only neutral histidine and deprotonated cysteine and selenocysteine are able to effectively replace the chloride ligand in AP-1.
Assuntos
Trióxido de Arsênio/análogos & derivados , Cisplatino/análogos & derivadosRESUMO
Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6) regulates a variety of malignant properties of cancer cells. It is known that endothelial cells promote tumor progression and chemoresistance. The present study aimed to investigate the roles of LPA5 in cellular functions modulated by endothelial cells and anticancer drug in osteosarcoma cells. Human osteosarcoma MG-63 cells were maintained in endothelial F2 cell supernatants. After culturing for 3 months, MG63-F2 cells were established. LPAR5 expression level in MG63-F2 cells was significantly elevated, compared with MG-63 cells. The cell motile activity of MG63-F2 cells was markedly higher than that of MG-63 cells. To validate the effects of LPA5 on cell motile activity, LPA5 knockdown cells were generated from MG-63 cells. The cell motile activity of MG-63 cells was inhibited by LPA5 knockdown. The cell survival to cisplatin (CDDP) was reduced in MG-63 cells treated with LPA. In the presence of LPA, the cell survival rate was significantly lower in MG63-F2 cells than MG-63 cells, correlating with LPAR5 expression. LPA5 knockdown cells indicated the high cell survival rate to CDDP. Moreover, LPAR5 expression level was increased in the long-term CDDP treated MG63-C cells. The cell survival to CDDP of MG63-C cells was enhanced by LPA5 knockdown. These results suggest that cellular functions are regulated through LPA5-mediatd signaling induced by endothelial cells and CDDP in MG-63 cells.
Assuntos
Células Endoteliais/metabolismo , Osteossarcoma/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Meios de Cultivo Condicionados/farmacologia , Humanos , Lisofosfolipídeos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount of AP-1 trapped inside the cage. The X-ray structure of AP-1-encapsulated AFt was solved at 1.50 Å. Diffraction data revealed that an AP-1 fragment coordinates the side chain of a His residue. The biological activity of AP-1-loaded AFt was comparatively tested on a few representative cancer and non-cancer cell lines. Even though the presence of the cage reduces the overall cytotoxicity of AP-1, it improves its selectivity towards cancer cells.
Assuntos
Antineoplásicos , Trióxido de Arsênio/análogos & derivados , Cisplatino/análogos & derivados , Citotoxinas , Ferritinas , Neoplasias/tratamento farmacológico , Compostos de Platina , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Trióxido de Arsênio/química , Trióxido de Arsênio/farmacologia , Células 3T3 BALB , Cisplatino/química , Cisplatino/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Ferritinas/química , Ferritinas/farmacologia , Humanos , Camundongos , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Compostos de Platina/química , Compostos de Platina/farmacologia , Relação Estrutura-AtividadeRESUMO
Although Pt(II)-based drugs are widely used to treat cancer, very few molecules have been approved for routine use in chemotherapy due to their side-effects on healthy tissues. A new approach to reducing the toxicity of these drugs is generating a prodrug by increasing the oxidation state of the metallic center to Pt(IV), a less reactive form that is only activated once it enters a cell. We used theoretical tools to combine the parent Pt(IV) prodrug, oxoplatin, with the most recent FDA-approved anti-cancer drug set published by the National Institute of Health (NIH). The only prerequisite imposed for the latter was the presence of one carboxylic group in the structure, a chemical feature that ensures a link to the coordination sphere via a simple esterification procedure. Our calculations led to a series of bifunctional prodrugs ranked according to their relative stabilities and activation profiles. Of all the designed molecules, the combination of oxoplatin with aminolevulinic acid as the bioactive ligand emerged as the most promising strategy by which to design enhanced dual-potency oncology drugs.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/análogos & derivados , Pró-Fármacos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/química , Cisplatino/farmacocinética , Simulação por Computador , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , TermodinâmicaRESUMO
A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity.
Assuntos
Ácidos e Sais Biliares/química , Cisplatino/análogos & derivados , Compostos de Platina/síntese química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Células MCF-7 , Estrutura Molecular , Compostos de Platina/química , Compostos de Platina/farmacologiaRESUMO
Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor cell lines reveal that arsenoplatin-1 (AP-1), [Pt(µ-NHC(CH3)O)2ClAs(OH)2], the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomolecules-proteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nε of His in a manner that preserves the Pt-As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt-As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt-As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
Assuntos
Antineoplásicos/farmacologia , Trióxido de Arsênio/análogos & derivados , Cisplatino/análogos & derivados , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Trióxido de Arsênio/química , Trióxido de Arsênio/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organoplatínicos/química , Relação Estrutura-AtividadeRESUMO
Black phosphorus (BP) is a two-dimensional (2D) nanomaterial with high charge-carrier mobility, a tunable direct bandgap, and a unique in-plane anisotropic structure; however, the easiness of BP oxidation into P xO y species in ambient conditions largely limits its applications. In this study, modified cisplatin-Pt-NO3 [Pt(NH3)2(NO3)2] is used for surface coordination with BP nanosheets to generate Pt@BP, which maintains the surface morphology and properties of BP nanosheets for more than 24 h in ambient conditions. In addition, Pt@BP interacts with DNA both in vitro and in cell. Pt@BP shows a good cellular uptake rate and significantly increases the drug sensitivity of cisplatin-resistant cancer cell lines (A2780 and HepG2) compared with unmodified cisplatin. Our study is the first attempt to stabilize bare BP with cationic cisplatin species, and the generated Pt@BP could be used for potential synergistic photothermal/chemotherapy of cisplatin-resistant cancer.
Assuntos
Antineoplásicos/química , Cisplatino/análogos & derivados , Fósforo/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/síntese química , Cisplatino/farmacologia , Humanos , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fósforo/farmacologiaRESUMO
BACKGROUND: Cisplatin has been widely used for the treatment of cancer and its antitumour activity is attributed to its capacity to form DNA adducts, predominantly at guanine residues, which impede cellular processes such as DNA replication and transcription. However, there are associated toxicity and drug resistance issues which plague its use. This has prompted the development and screening of a range of chemotherapeutic drug analogues towards improved efficacy. The biological properties of three novel platinum-based compounds consisting of varying cis-configured ligand groups, as well as a commercially supplied compound, were characterised in this study to determine their potential as anticancer agents. METHODS: The linear amplification reaction was employed, in conjunction with capillary electrophoresis, to quantify the sequence specificity of DNA adducts induced by these compounds using a DNA template containing telomeric repeat sequences. Additionally, the DNA interstrand cross-linking and unwinding efficiency of these compounds were assessed through the application of denaturing and native agarose gel electrophoresis techniques, respectively. Their cytotoxicity was determined in HeLa cells using a colorimetric cell viability assay. RESULTS: All three novel platinum-based compounds were found to induce DNA adduct formation at the tandem telomeric repeat sequences. The sequence specificity profile at these sites was characterised and these were distinct from that of cisplatin. Two of these compounds with the enantiomeric 1,2-diaminocyclopentane ligand (SS and RR-DACP) were found to induce a greater degree of DNA unwinding than cisplatin, but exhibited marginally lower DNA cross-linking efficiencies. Furthermore, the RR-isomer was more cytotoxic in HeLa cells than cisplatin. CONCLUSIONS: The biological characteristics of these compounds were assessed relative to cisplatin, and a variation in the sequence specificity and a greater capacity to induce DNA unwinding was observed. These compounds warrant further investigations towards developing more efficient chemotherapeutic drugs.
Assuntos
Adutos de DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/química , Cisplatino/análogos & derivados , Cisplatino/química , Cisplatino/uso terapêutico , Reagentes de Ligações Cruzadas , DNA/química , Dano ao DNA/efeitos dos fármacos , Células HeLa , Humanos , Conformação de Ácido Nucleico/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Platina/química , Platina/uso terapêutico , EstereoisomerismoRESUMO
The therapeutic use of cisplatin for the treatment of solid tumours is associated with organ toxicity. Amongst those, the cardiotoxicity is an occasional but very serious and severe side effect. To prevent or reduce these negative effects, many cisplatin analogues have been synthesized and evaluated in terms of being a less toxic and more effective agent. In present study, we examined the effects of cisplatin and its three analogues in the isolated rat heart to determine whether changes in the structure of the platinum complexes (changing of carrier ligands - ethylenediamine; 1,2-diaminocyclohexane; 2,2':6',2''-terpyridine) can influence their cardiotoxic effects. The results of our research indicate that the introduction of aromatic rings in the structure of the platinum complexes has a negative influence on the heart function. Conversely, the other two examined complexes had less negative effects on heart function compared to cisplatin. Our findings may be of interest for a possible synthetic strategy of introducing a carrier ligand that will exert a less cardiotoxic effect.
Assuntos
Cisplatino/análogos & derivados , Cisplatino/efeitos adversos , Circulação Coronária/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiologia , Perfusão , Animais , Relação Dose-Resposta a Droga , Hemodinâmica/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Three new crystal structures containing [PtCl6]2−, pyridinium and benzimidazole groups have been prepared: [PtCl6]·(H-bzm)2·2(H2O) (1), [PtCl6]·(H-bipy)2·2(H2O) (2), [PtCl6]·(H-dimethyl-bipy)2·2(H2O) (3) [H-bzm: benzimidazole cation, H-bipy: 2,2'-bipyridine cation, H-dimethyl-bipy: 4,4'-bimethyl-2,2'-bipyridine cation]. All compounds have been fully characterized by elemental analyses, single-crystal X-ray analyses, IR spectra, TG analyses, and fluorescence studies. Single-crystal X-ray diffraction analysis suggests that the primary synthon contains âºNâ»H···Cl−, including ionic bonding and hydrogen bonding interactions. The dimensions are enhanced further by secondary Oâ»H ââCl and Nâ»H ââO hydrogen bonding interactions between donor and acceptor atoms located at the periphery of these synthons. Moreover, coulombic attractions between the ions play an important role in reinforcing the structures of these complexes. In addition, antitumor activity against human lung adenocarcinoma cell line (A549) and human nasopharyngeal carcinoma cell line (CNE-2) was performed. These complexes all showed inhibition to the two cell lines, while complex 3 exhibited higher efficiency than complexes 1â»2.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Compostos Heterocíclicos/química , Compostos Inorgânicos/química , Nitrogênio/química , Compostos Orgânicos/química , Antineoplásicos/síntese química , Cátions , Cisplatino/síntese química , Cisplatino/química , Cisplatino/farmacologia , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular , Espectrofotometria Ultravioleta , TermogravimetriaRESUMO
Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity.
Assuntos
Antineoplásicos/química , Antineoplásicos/toxicidade , Cisplatino/análogos & derivados , Cisplatino/toxicidade , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Animais , Biotina/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Rim/citologia , Rim/patologia , Nefropatias/patologia , Células LLC-PK1 , Proteômica , SuínosRESUMO
As part of a comprehensive study of N-unsubstituted bispidines, the novel 9,9-difluorobispidine (D) has been synthesized. The compound crystallizes from pentane below 0 °C in the ordered-crystalline phase D-II and undergoes at 0-30 °C a stepwise endothermic phase transition to a dynamically disordered crystalline phase D-I; melting occurs at 227 °C. Single crystalline D-II has been subjected to X-ray structure analysis, revealing association of the molecules to form chains. Reaction of (1,5-hexadiene)PtCl2 with D affords {C7H10F2(NH)2}PtCl2 (D1), which can be converted by conventional routes to {C7H10F2(NH)2}Pt(cbdca)·5H2O (D2) and {C7H10F2(NH)2}Pt(C2O4) (D3). Compound D1 crystallizes solvent-free from water and is isomorphous to the solvent-free parent bispidine analogue (A1). The pentahydrate D2 is isomorphous to the bispidine and 9-oxabispidine homologues (A2 and C2), as shown by X-ray structure analyses. An increased polarity of the bispidine skeleton as a consequence of the high electronegativity of fluorine is seen as the reason for low cytotoxic potency of D1-D3.
Assuntos
Carboplatina/química , Cisplatino/química , Compostos Organoplatínicos/química , Carboplatina/análogos & derivados , Carboplatina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Humanos , Conformação Molecular , Compostos Organoplatínicos/farmacologia , OxaliplatinaRESUMO
Cisplatin is the most widely used anticancer drug in the world. Mono-chloro and none-chloro complexes of cisplatin may be believed to be the activated compounds. The separation of these compounds using octa decyl silyl column or aminopropylsilyl silica gel column is difficult because of high-reactivity and structural similarity. In this study, cisplatin, hydroxo complexes, and OH-dimer were determined by HPLC using a naphthylethyl group bonded with silica gel (πNAP) column. The analytical conditions of HPLC were as follows: analytical column, πNAP column; wave length, 225 nm; column temperature, 40°C; mobile phase, 0.1 M sodium perchlorate, acetonitrile, and perchloric acid (290 : 10 : 3), flow rate, 1.0 mL/min. Sample (20 µL) was injected onto the HPLC system. Retention time of cisplatin, mono-chloride, OH-dimer, and none-chloride was 3.2, 3.4, 3.6, and, 4.3-6.6 min, respectively. Measurable ranges with this method were 1×10-5 to 4×10-3 M for cisplatin. Correlation coefficient of the calibration curves of cisplatin was 0.999 (p<0.01). The within- and between-day variations of coefficient of variation (CV) were 5% or lower. In this study, injectable formulations in physiological saline solution, water for injection, 5% glucose solution, and 7% sodium bicarbonate precisely were measured the stability and compositional changes upon mixing by πNAP column rather than C18 column. We successfully determined cisplatin, hydroxo complexes, and OH-dimer by HPLC using a πNAP column. Thus the measurement of cisplatin (cis-diamminedichloro-platinum(II), cis-[PtCl2(NH3)2]) (CDDP) should be done using a πNAP column rather than a C18 column or aminopropylsilyl silica gel column.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cisplatino/análise , Antineoplásicos/análise , Cisplatino/análogos & derivados , Cisplatino/química , Indicadores e Reagentes , Estrutura Molecular , Sílica Gel , Tecnologia Farmacêutica/métodosRESUMO
Cisplatin derivatives can form various types of DNA lesions (DNA-Pt) and trigger pleiotropic DNA damage responses. Here, we report a strategy to visualize DNA-Pt with high resolution, taking advantage of a novel azide-containing derivative of cisplatin we named APPA, a cellular pre-extraction protocol and the labeling of DNA-Pt by means of click chemistry in cells. Our investigation revealed that pretreating cells with the histone deacetylase (HDAC) inhibitor SAHA led to detectable clusters of DNA-Pt that colocalized with the ubiquitin ligase RAD18 and the replication protein PCNA. Consistent with activation of translesion synthesis (TLS) under these conditions, SAHA and cisplatin cotreatment promoted focal accumulation of the low-fidelity polymerase Polη that also colocalized with PCNA. Remarkably, these cotreatments synergistically triggered mono-ubiquitination of PCNA and apoptosis in a RAD18-dependent manner. Our data provide evidence for a role of chromatin in regulating genome targeting with cisplatin derivatives and associated cellular responses.
Assuntos
Antineoplásicos/farmacologia , Cromatina/fisiologia , Cisplatino/farmacologia , Genoma Humano/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/análogos & derivados , Química Click , DNA/efeitos dos fármacos , Dano ao DNA , DNA Polimerase Dirigida por DNA/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Sondas Moleculares , Antígeno Nuclear de Célula em Proliferação/metabolismo , UbiquitinaçãoRESUMO
Here, a nanoparticle-mediated delivery of multinuclear platinum(IV) prodrugs [biodegradable polymer-di-cisPt(IV)] for overcoming cisplatin drug resistance is reported. From the MTT assays, lower IC50 values of polymer-di-cisPt(IV) on A2780DDP cells than A2780 were observed with the lowest resistance factor of 0.7. Inductively coupled plasma mass spectroscopy results showed that more drugs were delivered into cancer cells and greater number of Pt-DNA adducts were formed with the use of the polymer-di-cisPt(IV) conjugate nanoparticles. By a mechanistic study with endocytosis inhibitors to treat A2780 cells, we proved that polymer-di-cisPt(IV) conjugate nanoparticles were internalized by the cancer cells through endocytosis rather than through passive diffusion or copper transporter 1-mediated active transportation. This well illustrates the way how the polymer-di-cisPt(IV) micelles overcome cisplatin resistance.
Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/análogos & derivados , Cisplatino/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Nanopartículas , Pró-Fármacos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Cisplatino/química , Cisplatino/metabolismo , Portadores de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Micelas , Poliésteres/química , Polilisina/química , Pró-Fármacos/química , Pró-Fármacos/metabolismoRESUMO
PURPOSE: Cisplatin, is recognized as a first line therapeutic for the treatment of non-small cell lung cancer (NSCLC). Cisplatin resistance is identified as the most detrimental complication during treatment and has been associated with upregulation of several genes, such as the anti-apoptotic gene survivin. In this study, we have evaluated the cytotoxic activity of lipid (C6 and C8)-modified platinum compounds in combination with a survivin-silencing siRNA against cisplatin resistant tumors. METHODS: We synthesized and characterized several lipid-modified platinum compounds and evaluated their cytotoxic activity alone or in combination with survivin-silencing siRNA in vitro and in vivo against A549DDP cells and in vivo in tumor xenograft model. RESULTS: The lipid-modified compounds exhibited significantly stronger cytotoxic activity in vitro compared to cisplatin, with CDDP-C6 and CDDP-C8 producing the most pronounced effect, in both A549 and A549DDP cells. Pre-treatment of the A549DDP cells with survivin-silencing siRNA enhanced the cytotoxic activity of these compounds. In vivo, the co-treatment of the survivin-silencing siRNA and CDDP-C8 produced the strongest tumor growth inhibition effect (64.5%, p < 0.05) on a cancer mouse model of chemoresistant lung cancer. In contrast, cisplatin treatment exhibited no significant tumor growth inhibition (4.5%, no p). CONCLUSIONS: Co-treatment of lipid-modified compounds and survivin-silencing siRNA can constitute a reliable alternative to cisplatin treatment for cisplatin-resistant lung tumors that merit further evaluation.
Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/análogos & derivados , Cisplatino/uso terapêutico , Proteínas Inibidoras de Apoptose/genética , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , RNA Interferente Pequeno/genética , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Inativação Gênica , Humanos , Ácido Hialurônico/química , Neoplasias Pulmonares/genética , Camundongos Nus , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoimina/química , SurvivinaRESUMO
The literature synthesis of 9-oxabispidine [OC6H10(NH)2, C] has been revisited and optimized, which includes determination of the crystal structures of C, the secondary component trans-(PhSO2)NC4H6O(CH2I)2 (trans-III), and the unexpected solute intermediate OC6H10(NSO2Ph)2·(1)/2py (V·(1)/2py). The reaction of (1,5-hexadiene)platinum dichloride with C yields {OC6H10(NH)2}PtCl2 (C1), which is converted to {OC6H10(NH)2}Pt(cbdca)·5H2O (C2) and {OC6H10(NH)2}Pt(C2O4) (C3). In the crystal, C1 forms a planar 2D network by N-H··Cl and N-H··O hydrogen bonding. In the crystal structure of C2, which is isomorphous to the parent bispidine compound (A2), all complex molecules are encapsulated by a water shell. While complexes C1 and C3 are virtually insoluble in water, C2 dissolves quite well. The low cytotoxicity of compounds C1-C3 is explained by an increased polarity of the bonds in the C skeleton as a consequence of the electronegative O atom.
Assuntos
Antineoplásicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Carboplatina/análogos & derivados , Cisplatino/análogos & derivados , Compostos Organoplatínicos/química , Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Carboplatina/síntese química , Técnicas de Química Sintética , Cisplatino/síntese química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Compostos Organoplatínicos/síntese química , OxaliplatinaRESUMO
This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5'-CpG sequences. Their binding to methylated and non-methylated 5'-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5'-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5'-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell's genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use.
Assuntos
Aminacrina/farmacologia , Cisplatino/farmacologia , DNA/metabolismo , Substâncias Intercalantes/farmacologia , Compostos Organoplatínicos/farmacologia , Aminacrina/análogos & derivados , Cisplatino/análogos & derivados , Ilhas de CpG/efeitos dos fármacos , DNA/química , Metilação de DNA , Substâncias Intercalantes/química , Compostos Organoplatínicos/química , Plasmídeos/química , Plasmídeos/metabolismoRESUMO
Isolated molecular clusters of adenine, cytosine, thymine and uracil bound to hexachloroplatinate, PtCl6(2-), have been studied using laser electronic photodissociation spectroscopy to investigate photoactivation of a platinum complex in the vicinity of a nucleobase. These metal complex-nucleobase clusters represent model systems for identifying the fundamental photochemical processes occurring in photodynamic platinum drug therapies that target DNA. This is the first study to explore the specific role of a strongly photoactive platinum compound in the aggregate complex. Each of the clusters studied displays a broadly similar absorption spectra, with a strong λmax â¼ 4.6 eV absorption band and a subsequent increase in the absorption intensity towards higher spectral-energy. The absorption bands are traced to ligand-to-metal-charge-transfer excitations on the PtCl6(2-) moiety within the cluster, and result in Cl(-)·nucleobase and PtCl5(-) as primary photofragments. These results demonstrate how selective photoexcitation can drive distinctive photodecay channels for a model photo-pharmaceutical. In addition, cluster absorption due to excitation of nucleobase-centred chromophores is observed in the region around 5 eV. For the uracil cluster, photofragments consistent with ultrafast decay of the excited state and vibrational predissociation on the ground-state surface are observed. However, this decay channel becomes successively weaker on going from thymine to cytosine to adenine, due to differential coupling of the excited states to the electron detachment continuum. These effects demonstrate the distinctive photophysical characteristics of the different nucleobases, and are discussed in the context of the recently recorded photoelectron spectra of theses clusters.
Assuntos
Adenina/metabolismo , Cisplatino/análogos & derivados , Citosina/metabolismo , Radiossensibilizantes/farmacologia , Timina/metabolismo , Uracila/metabolismo , Cisplatino/química , Cisplatino/farmacologia , Lasers , Modelos Moleculares , Processos Fotoquímicos , Radiossensibilizantes/química , Raios UltravioletaRESUMO
The reactivity of a bispidine, 3,7-diazabicyclo[3.3.1]nonane, analogue of cisplatin, a new anticancer drug with promising properties, is theoretically investigated to clarify the in vitro reactivity and in vivo mechanism of action of this compound. Thermodynamics and kinetics of the first and second aquation steps and of the reaction of the generated mono- and diaqua species with guanine, the main target of the platinum based antitumor compounds, have been studied. In agreement with the experimental evidence, the bispidine analogue is significantly less reactive than cisplatin toward aquation but the formed aquaspecies show a good reactivity with guanine, consistently with the promising anticancer properties of these new compounds.