RÉSUMÉ
IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC)2-Fe2+-NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo.
Sujet(s)
Monoxyde d'azote , Oximes , Quinoxalines , Spectroscopie de résonance de spin électronique/méthodes , Animaux , Monoxyde d'azote/métabolisme , Oximes/composition chimique , Oximes/pharmacologie , Rats , Quinoxalines/composition chimique , Quinoxalines/pharmacologie , Foie/métabolisme , Foie/effets des médicaments et des substances chimiques , Mâle , Hémoglobines/métabolisme , Donneur d'oxyde nitrique/pharmacologie , Donneur d'oxyde nitrique/composition chimique , Acide diéthyl-dithiocarbamique/pharmacologie , Acide diéthyl-dithiocarbamique/composition chimiqueRÉSUMÉ
Hepatitis B Virus (HBV) infection significantly elevates the risk of hepatocellular carcinoma (HCC), with the HBV X protein (HBx) playing a crucial role in cancer progression. Sorafenib, the primary therapy for advanced HCC, shows limited effectiveness in HBV-infected patients due to HBx-related resistance. Numerous studies have explored combination therapies to overcome this resistance. Sodium diethyldithiocarbamate (DDC), known for its anticancer effects and its inhibition of superoxide dismutase 1 (SOD1), is hypothesized to counteract sorafenib (SF) resistance in HBV-positive HCCs. Our research demonstrates that combining DDC with SF significantly reduces HBx and SOD1 expressions in HBV-positive HCC cells and human tissues. This combination therapy disrupts the PI3K/Akt/mTOR signalling pathway and promotes apoptosis by increasing reactive oxygen species (ROS) levels. These cellular changes lead to reduced tumour viability and enhanced sensitivity to SF, as evidenced by the synergistic suppression of tumour growth in xenograft models. Additionally, DDC-mediated suppression of SOD1 further enhances SF sensitivity in HBV-positive HCC cells and xenografted animals, thereby inhibiting cancer progression more effectively. These findings suggest that the DDC-SF combination could serve as a promising strategy for overcoming SF resistance in HBV-related HCC, potentially optimizing therapy outcomes.
Sujet(s)
Carcinome hépatocellulaire , Virus de l'hépatite B , Tumeurs du foie , Phosphatidylinositol 3-kinases , Protéines proto-oncogènes c-akt , Espèces réactives de l'oxygène , Transduction du signal , Sorafénib , Superoxide dismutase-1 , Sérine-thréonine kinases TOR , Sorafénib/pharmacologie , Sorafénib/usage thérapeutique , Humains , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/virologie , Tumeurs du foie/métabolisme , Tumeurs du foie/anatomopathologie , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/virologie , Carcinome hépatocellulaire/métabolisme , Carcinome hépatocellulaire/anatomopathologie , Espèces réactives de l'oxygène/métabolisme , Protéines proto-oncogènes c-akt/métabolisme , Superoxide dismutase-1/métabolisme , Superoxide dismutase-1/génétique , Animaux , Sérine-thréonine kinases TOR/métabolisme , Sérine-thréonine kinases TOR/antagonistes et inhibiteurs , Phosphatidylinositol 3-kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Souris , Virus de l'hépatite B/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Tests d'activité antitumorale sur modèle de xénogreffe , Apoptose/effets des médicaments et des substances chimiques , Hépatite B/complications , Hépatite B/traitement médicamenteux , Hépatite B/virologie , Acide diéthyl-dithiocarbamique/pharmacologie , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Souris nude , Prolifération cellulaire/effets des médicaments et des substances chimiques , Transactivateurs , Protéines virales régulatrices ou accessoiresRÉSUMÉ
Mitochondria can contact lipid droplets (LDs) to form peridroplet mitochondria (PDM) which trap fatty acids in LDs by providing ATP for triglyceride synthesis and prevent lipotoxicity. However, the role of PDM in metabolic dysfunction associated steatotic liver disease (MASLD) is not clear. Here, the features of PDM in dietary MASLD models with different severity in mice were explored. Electron microscope photographs show that LDs and mitochondria rarely come into contact with each other in normal liver. In mice fed with high-fat diet, PDM can be observed in the liver as early as the beginning of steatosis in hepatocytes. For the first time, we show that PDM in mouse liver varies with the severity of MASLD. PDM and cytosolic mitochondria were isolated from the liver tissue of MASLD and analyzed by quantitative proteomics. Compared with cytosolic mitochondria, PDM have enhanced mitochondrial respiration and ATP synthesis. Diethyldithiocarbamate (DDC) alleviates choline-deficient, L-amino acid-defined diet-induced MASLD, while increases PDM in the liver. Similarly, DDC promotes the contact of mitochondria-LDs in steatotic C3A cells in vitro. Meanwhile, DDC promotes triglyceride synthesis and improves mitochondrial dysfunction in MASLD. In addition, DDC upregulates perilipin 5 both in vivo and in vitro, which is considered as a key regulator in PDM formation. Knockout of perilipin 5 inhibits the contact of mitochondria-LDs induced by DDC in C3A cells. These results demonstrate that PDM might be associated with the progression of MASLD and the prevention of MASLD by DDC.
Sujet(s)
Acide diéthyl-dithiocarbamique , Mitochondries , Animaux , Souris , Acide diéthyl-dithiocarbamique/pharmacologie , Mitochondries/métabolisme , Mitochondries/effets des médicaments et des substances chimiques , Mâle , Stéatose hépatique/métabolisme , Stéatose hépatique/prévention et contrôle , Stéatose hépatique/anatomopathologie , Gouttelettes lipidiques/métabolisme , Gouttelettes lipidiques/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Mitochondries du foie/métabolisme , Mitochondries du foie/effets des médicaments et des substances chimiques , Humains , Alimentation riche en graisse/effets indésirablesRÉSUMÉ
Background: Cancer stem cells' (CSCs) resistance to 5-fluorouracil (Fu), which is the main obstacle in treating colon cancer (CC), can be overcome by ferroptosis. The latter, herein, can be triggered by FeO nanoparticles (inducer of iron accumulation) and diethyldithiocarbamate-inhibited glutathione system and aldehyde dehydrogenase (ALDH1A1-maintained stemness, therapeutic resistance and metastasis). Materials & methods: Nanocomplex of FeO nanoparticles and diethyldithiocarbamate (FD) was used in combination with Fu to investigate its potential synergistic anti-CSC influence using CC spheroid models. Results: In Fu + FD-treated spheroids, the strongest growth inhibition, the highest cell death percentage, and the lowest CD133+-CSCs percentage and stemness gene expressions (e.g., drug efflux transporter), and the strongest antimetastatic effect were recorded with high synergistic indexes. Conclusion: Fu + FD represents effective combination therapy for chemoresistant CC cells.
[Box: see text].
Sujet(s)
Tumeurs du côlon , Acide diéthyl-dithiocarbamique , Synergie des médicaments , Fluorouracil , Cellules souches tumorales , Sphéroïdes de cellules , Humains , Tumeurs du côlon/traitement médicamenteux , Tumeurs du côlon/anatomopathologie , Tumeurs du côlon/métabolisme , Fluorouracil/pharmacologie , Fluorouracil/composition chimique , Acide diéthyl-dithiocarbamique/pharmacologie , Acide diéthyl-dithiocarbamique/composition chimique , Sphéroïdes de cellules/effets des médicaments et des substances chimiques , Cellules souches tumorales/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Nanoparticules magnétiques d'oxyde de fer/composition chimique , Prolifération cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
Animal tumors serve as reasonable models for human cancers. Both human and animal tumors often reveal triplet EPR signals of nitrosylhemoglobin (HbNO) as an effect of nitric oxide formation in tumor tissue, where NO is complexed by Hb. In search of factors determining the appearance of nitrosylhemoglobin (HbNO) in solid tumors, we compared the intensities of electron paramagnetic resonance (EPR) signals of various iron-nitrosyl complexes detectable in tumor tissues, in the presence and absence of excess exogenous iron(II) and diethyldithiocarbamate (DETC). Three types of murine tumors, namely, L5178Y lymphoma, amelanotic Cloudman S91 melanoma, and Ehrlich carcinoma (EC) growing in DBA/2 or Swiss mice, were used. The results were analyzed in the context of vascularization determined histochemically using antibodies to CD31. Strong HbNO EPR signals were found in melanoma, i.e., in the tumor with a vast amount of a hemorrhagic necrosis core. Strong Fe(DETC)2NO signals could be induced in poorly vascularized EC. In L5178Y, there was a correlation between both types of signals, and in addition, Fe(RS)2(NO)2 signals of non-heme iron-nitrosyl complexes could be detected. We postulate that HbNO EPR signals appear during active destruction of well-vascularized tumor tissue due to hemorrhagic necrosis. The presence of iron-nitrosyl complexes in tumor tissue is biologically meaningful and defines the evolution of complicated tumor-host interactions.
Sujet(s)
Acide diéthyl-dithiocarbamique , Hémoglobines , Monoxyde d'azote , Animaux , Monoxyde d'azote/métabolisme , Acide diéthyl-dithiocarbamique/pharmacologie , Acide diéthyl-dithiocarbamique/composition chimique , Souris , Hémoglobines/métabolisme , Hémoglobines/composition chimique , Spectroscopie de résonance de spin électronique/méthodes , Piégeage de spin/méthodes , Néovascularisation pathologique/métabolisme , Lignée cellulaire tumorale , Modèles animaux de maladie humaine , Souris de lignée DBA , Composés du fer II/composition chimiqueRÉSUMÉ
Malignant tumors are still one of the most deadly diseases that threaten human life and health. However, developing new drugs is challenging due to lengthy trials, funding constraints, and regulatory approval procedures. Consequently, researchers have devoted themselves to transforming some clinically approved old drugs into antitumor drugs with certain active ingredients, which have become an attractive alternative. Disulfiram (DSF), an antialcohol medication, can rapidly metabolize in the physiological environment into diethyldithiocarbamate (DTC) which can readily react with Cu2+ ions in situ to form the highly toxic bis(N,N-diethyldithiocarbamate)-copper(II) (CuET) complex. In this study, DSF is loaded into mesoporous dopamine nanocarriers and surface-chelated with tannin and Cu2+ to construct M-MDTC nanoprodrugs under the camouflage of K7 tumor cell membranes. After intravenous injection, M-MDTC nanoprodrugs successfully reach the tumor sites with the help of mediated cell membranes. Under slightly acidic pH and photothermal stimulation conditions, DSF and Cu2+ are simultaneously released, forming a highly toxic CuET to kill tumor cells in situ. The generated CuET can also induce immunogenic cell death of tumor cells, increase the proportion of CD86+ CD80+ cells, and promote dendritic cell maturation. In vitro and in vivo studies of M-MDTC nanoprodrugs have shown excellent tumor-cell-killing ability and solid tumor suppression. This approach enables in situ amplification of chemotherapy in the tumor microenvironment, achieving an effective antitumor treatment.
Sujet(s)
Cadavérine/analogues et dérivés , Cuivre , Tumeurs , Humains , Lignée cellulaire tumorale , Cuivre/pharmacologie , Cuivre/usage thérapeutique , Microenvironnement tumoral , Biomimétique , Disulfirame/pharmacologie , Acide diéthyl-dithiocarbamique/pharmacologie , Acide diéthyl-dithiocarbamique/usage thérapeutique , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologieRÉSUMÉ
Gold-based nanoparticles hold promise as functional nanomedicines, including in combination with a photothermal effect for cancer therapy in conjunction with chemotherapy. Here, we synthesized hollow gold nanoparticles (HGNPs) exhibiting efficient light absorption in the near-IR (NIR) region. Several synthesis conditions were explored and provided monodisperse HGNPs approximately 95-135 nm in diameter with a light absorbance range of approximately 600-720 nm. The HGNPs were hollow and the surface had protruding structures when prepared using high concentrations of HAuCl4. The simultaneous nucleation of a sacrificial AgCl template and Au nanoparticles may affect the resulting HGNPs. Diethyldithiocarbamate (DDTC) is metabolized from disulfiram and is a repurposed drug currently attracting attention. The chelation of DDTC with copper ion (DDTC-Cu) has been investigated for treating glioma, and here we confirmed the cytotoxic effect of DDTC-Cu towards rat C6 glioma cells in vitro. HGNPs alone were biocompatible and showed little cytotoxicity, whereas a mixture of DDTC-Cu and HGNPs was cytotoxic in a dose dependent manner. The temperature of HGNPs was increased by NIR-laser irradiation. The photothermal effect on HGNPs under NIR-laser irradiation resulted in cytotoxicity towards C6 cells and was dependent on the irradiation time. Photothermal therapy by HGNPs combined and DDTC-Cu was highly effective, suggesting that this combination approach hold promise as a future glioma therapy.
Sujet(s)
Antinéoplasiques , Gliome , Nanoparticules métalliques , Animaux , Rats , Acide diéthyl-dithiocarbamique/pharmacologie , Cuivre , Or , Thérapie photothermique , Antinéoplasiques/pharmacologie , Lignée cellulaire , Gliome/traitement médicamenteuxRÉSUMÉ
The Cu2+ complex formed by the coordination of disulfiram (DSF) metabolite diethyldithiocarbamate (DTC), Cu(DTC)2, can effectively inhibit tumor growth. However, insufficient Cu2+ levels in the tumor microenvironment can impact tumor-suppressive effects of DTC. In this study, we proposed a Cu2+ and DSF tumor microenvironment-targeted delivery system. This system utilizes hollow mesoporous silica (HMSN) as a carrier, after loading with DSF, encases it using a complex of tannic acid (TA) and Cu2+ on the outer layer. In the slightly acidic tumor microenvironment, TA/Cu undergoes hydrolysis, releasing Cu2+ and DSF, which further form Cu(DTC)2 to inhibit tumor growth. Additionally, Cu2+ can engage in a Fenton-like reaction with H2O2 in the tumor microenvironment to form OH, therefore, chemodynamic therapy (CDT) and Cu(DTC)2 are used in combination for tumor therapy. In vivo tumor treatment results demonstrated that AHD@TA/Cu could accumulate at the tumor site, achieving a tumor inhibition rate of up to 77.6 %. This study offers a novel approach, circumventing the use of traditional chemotherapy drugs, and provides valuable insights into the development of in situ tumor drug therapies.
Sujet(s)
Acide diéthyl-dithiocarbamique , Tumeurs , Polyphénols , Humains , Acide diéthyl-dithiocarbamique/pharmacologie , Cuivre/pharmacologie , Silice/pharmacologie , Peroxyde d'hydrogène/métabolisme , Lignée cellulaire tumorale , Disulfirame/pharmacologie , Tumeurs/traitement médicamenteux , Microenvironnement tumoralRÉSUMÉ
Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@HES NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo. Furthermore, CuET@HES NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copperoxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis. As all components are widely used in clinics, CuET@HES NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines.
Sujet(s)
Carcinome hépatocellulaire , Tumeurs du foie , Nanoparticules , Humains , Acide diéthyl-dithiocarbamique/composition chimique , Acide diéthyl-dithiocarbamique/pharmacologie , Acide diéthyl-dithiocarbamique/usage thérapeutique , Cuivre/composition chimique , Nanoparticules/composition chimique , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/anatomopathologie , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/anatomopathologie , Amidon/composition chimique , Lignée cellulaire tumorale , Hydroxyéthylamidons/pharmacologie , Hydroxyéthylamidons/usage thérapeutique , Cellules souches tumoralesRÉSUMÉ
Metastatic tumor is initiated by metastatic seeds (cancer stem cells "CSCs") in a controlled redox microenvironment. Hence, an effective therapy that disrupts redox balance with eliminating CSCs is critical. Diethyldithiocarbamate (DE) is potent inhibitor of radical detoxifying enzyme (aldehyde dehydrogenase "ALDH"1A) causing effective eradication of CSCs. This DE effect was augmented and more selective by its nanoformulating with green synthesized copper oxide (Cu4O3) nanoparticles (NPs) and zinc oxide NPs, forming novel nanocomplexes of CD NPs and ZD NPs, respectively. These nanocomplexes exhibited the highest apoptotic, anti-migration, and ALDH1A inhibition potentials in M.D. Anderson-metastatic breast (MDA-MB) 231 cells. Importantly, these nanocomplexes revealed more selective oxidant activity than fluorouracil by elevating reactive oxygen species with depleting glutathione in only tumor tissues (mammary and liver) using mammary tumor liver metastasis animal model. Due to higher tumoral uptake and stronger oxidant activity of CD NPs than ZD NPs, CD NPs had more potential to induce apoptosis, suppress hypoxia-inducing factor gene, and eliminate CD44+CSCs with downregulating their stemness, chemoresistance, and metastatic genes and diminishing hepatic tumor marker (α-fetoprotein). These potentials interpreted the highest tumor size reduction with complete eradicating tumor metastasis to liver in CD NPs. Consequently, CD nanocomplex revealed the highest therapeutic potential representing a safe and promising nanomedicine against the metastatic stage of breast cancer.
Sujet(s)
Tumeurs du foie , Tumeurs mammaires de l'animal , Oxyde de zinc , Animaux , Femelle , Humains , Aldehyde dehydrogenase , Acide diéthyl-dithiocarbamique/pharmacologie , Hypoxie foetale , Fluorouracil , Oxydants , Microenvironnement tumoral , Oxyde de zinc/pharmacologieRÉSUMÉ
Disulfiram (DSF), a drug for alcohol withdrawal, has attracted extensive scientific attention due to its potential to treat cancer. The metabolite of DSF, diethyl dithiocarbamate (DDTC), forms a Cu-DDTC complex in vivo with copper ions, which has been shown to be a proteasome inhibitor with high antitumor activity. However, the in vivo stability of Cu-DDTC complexes remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with high antitumor activity was prepared by using the nanoscale metal-organic framework (MOF) Cu-BTC as a carrier and loading diethyldithiocarbamate (DDTC) through coordination interaction. The results showed that Cu-BTC@DDTC had high drug loading and adequate stability, and exhibited DDTC-Cu(I) chemical valence characteristics and polycrystalline structure features. In vitro cytocompatibility investigation and animal xenograft tumor model evaluation demonstrated the anti-cancer potential of Cu-BTC@DDTC, especially the combination of Cu-BTC@DDTC with low-dose cisplatin showed significant antitumor effect and biosafety. This study provides a feasible protocol for developing antitumor drugs based on the drug repurposing strategy.
Sujet(s)
Alcoolisme , Ferroptose , Mélanome , Réseaux organométalliques , Syndrome de sevrage , Animaux , Humains , Acide diéthyl-dithiocarbamique/pharmacologie , Réseaux organométalliques/pharmacologie , Réseaux organométalliques/métabolisme , Disulfirame/pharmacologie , Disulfirame/métabolisme , Mélanome/traitement médicamenteux , Cuivre/composition chimique , Lignée cellulaire tumorale , Système y+ de transport d'acides aminésRÉSUMÉ
Copper diethyldithiocarbamate [Cu(DDC)2] is a promising anticancer agent. However, its poor water solubility is a significant obstacle to clinical application. In previous studies, we developed a stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)2 nanoparticle (NP) to address the drug delivery challenge. In the current study, we investigate the use of Cu(DDC)2 NP for treating P-glycoprotein (P-gp) mediated drug-resistant cancers. We tested its anticancer efficacy with extensive in vitro cell-based assays and in vivo xenograft tumor model. We also explored the mechanism of overcoming drug resistance by Cu(DDC)2 NP. Our results indicate that Cu(DDC)2 NP is not a substrate of P-gp and thus can avoid P-gp mediated drug efflux. Further, the Cu(DDC)2 NP does not inhibit the activity or the expression of P-gp.
Sujet(s)
Acide diéthyl-dithiocarbamique , Résistance aux médicaments antinéoplasiques , Tumeurs , Humains , Glycoprotéine P , Cuivre/pharmacologie , Acide diéthyl-dithiocarbamique/pharmacologie , Nanoparticules métalliques , Animaux , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
New anti-Entamoeba histolytica multistage drugs are needed because only one drug class, nitroimidazoles, is available for treating invasive disease, and it does not effectively eradicate the infective cyst stage. Zinc ditiocarb (ZnDTC), a main metabolite of the FDA-approved drug disulfiram, was recently shown to be highly effective against the invasive trophozoite stage. In this brief report, we show that ZnDTC is active against cysts, with similar potency to first-line cysticidal drug paromomycin.
Sujet(s)
Alcoolisme , Kystes , Entamoeba histolytica , Parasites , Animaux , Disulfirame/pharmacologie , Disulfirame/usage thérapeutique , Acide diéthyl-dithiocarbamique/métabolisme , Acide diéthyl-dithiocarbamique/pharmacologieRÉSUMÉ
Mortality rate of metastatic breast cancer is linked to cancer stem cells (CSCs)' aggressive features (chemoresistance to apoptosis and redox imbalance). Therefore, unique dual therapeutic strategy compacts CSCs with inducing oxidative stress-mediated nonapoptosis (ferroptosis), confers effective malignant tumor eradication. Diethyldithiocarbamate (DDC) is a potent inhibitor of CSC aldehyde dehydrogenase and lowers glutathione (GSH) which aggravate iron-dependent ferroptosis. Herein, nanoformulations of DDC with green chemically synthesized ferrous oxide nanoparticles (FeO NPs) and ferric oxide (Fe2O3 NPs) were prepared. Due to nanoparticle characters and synergistic effect between iron oxide NPs and DDC, nanocomplexes (DFeO NPs and DFe2O3 NPs, respectively) exhibited the strongest anti-metastatic cancer potency in vitro. Because of corresponding iron oxide nature, DFeO NPs demonstrated better therapeutic efficacy than DFe4O3 NPs, in mammary tumor liver metastasis-bearing mice, in terms of tumor size, histological analysis, immunostaining % of ki-67+ and caspase 3+, and gene expression of p53 and BCl2. The potent anti-tumor effect of DFeO nanocomplex is attributed to the maximum elevation of reactive oxygen species and lipid peroxidation (ferroptosis hall marker) with severe depletion of GSH and Nrf2 selectively in both tumor tissues, causing CSC eradication with halting metastatic activity. The latters were confirmed by lowering CD44+ % and gene expression of HIF-α, ß-catenin, Notch, ABCG2-mediated chemoresistance, and MMP9 with diminishing liver tumor marker. Moreover, this nanocomplex did not cause any abnormal alterations in histological and biochemical parameters, compared to healthy group. Therefore, the selective apoptotic and ferroptotic with anti-CSC effects of DFeO NPs open new safe avenue for metastatic tumor therapy.
Sujet(s)
Acide diéthyl-dithiocarbamique , Nanoparticules , Souris , Animaux , Acide diéthyl-dithiocarbamique/pharmacologie , Acide diéthyl-dithiocarbamique/composition chimique , Caspase-3/métabolisme , Espèces réactives de l'oxygène/métabolisme , bêta-Caténine/métabolisme , Matrix metalloproteinase 9/métabolisme , Facteur-2 apparenté à NF-E2/métabolisme , Protéine p53 suppresseur de tumeur , Antigène KI-67/métabolisme , Nanoparticules/composition chimique , Protéines proto-oncogènes c-bcl-2 , Glutathion/métabolisme , Aldehyde dehydrogenase/métabolisme , Fer , Nanoparticules magnétiques d'oxyde de ferRÉSUMÉ
The novel di-and triphenyltin(IV) dithiocarbamate compounds represented as RnSnL2 (where R = C4H9, C6H5; n = 2,3; L = N,N-dithiocarbamate), Ph2Sn(N,N-diisopropyldithiocarbamate) (OC1), Ph3Sn(N,N-diisopropyldithiocarbamate) (OC2), Ph2Sn(N,N-diallyldithiocarbamate) (OC3), Ph3Sn(N,N-diallyldithiocarbamate) (OC4), and Ph2Sn(N,N-diethyldithiocarbamate) (OC5) were assessed for their cytotoxicity in K562 human erythroleukemia cells. All compounds inhibited the growth of cells at low micromolar concentrations (<10 µM), and the mechanism underlying their antiproliferative effects on K562 cells was apoptosis, as corroborated by the exposure of plasma membrane phosphatidylserine. OC2, which showed the most promising antiproliferative activity, was selected for further analyses. The results demonstrated that OC2 induced apoptosis in K562 cells via an intrinsic mitochondrial pathway triggered upon DNA damage, an early apoptotic signal. Subsequently, OC2 produced excessive intracellular reactive oxygen species. The role of oxidative stress was corroborated by the significant reduction in GSH levels and percentage of apoptosis in NAC-pretreated cells. OC2 could arrest the cell cycle progression in the S phase. These new findings elucidate the antiproliferative potential of OC2 in the K562 human erythroleukemia cells and warrant further investigation, specifically to determine the exact signaling pathway underlying its antileukemic efficacy.
Sujet(s)
Leucémie érythroblastique aigüe , Apoptose , Altération de l'ADN , Acide diéthyl-dithiocarbamique/analogues et dérivés , Acide diéthyl-dithiocarbamique/métabolisme , Acide diéthyl-dithiocarbamique/pharmacologie , Humains , Cellules K562 , Leucémie érythroblastique aigüe/traitement médicamenteux , Leucémie érythroblastique aigüe/métabolisme , Mitochondries , Composés organiques de l'étain , Phosphatidylsérine/métabolisme , Espèces réactives de l'oxygène/métabolismeRÉSUMÉ
BACKGROUND: Dithiocarbamates and derivatives (including disulfiram, DSF) are currently investigated as antineoplastic agents. We have revealed earlier the ability of hydroxocobalamin (vitamin Ð12b) combined with diethyldithiocarbamate (DDC) to catalyze the formation of highly cytotoxic oxidized derivatives of DSF (DSFoxy, sulfones and sulfoxides). METHODS: Electron and fluorescent confocal microscopy, molecular biology and conventional biochemical techniques were used to study the morphological and functional responses of MCF-7 human breast cancer cells to treatment with DDC and B12b alone or in combination. RESULTS: DDC induces unfolded protein response in MCF-7 cells. The combined use of DDC and B12b causes MCF-7 cell death. Electron microscopy revealed the separation of ER and nuclear membranes, leading to the formation of both cytoplasmic and perinuclear vacuoles, with many fibers inside. The process of vacuolization coincided with the appearance of ER stress markers, a marked damage to mitochondria, a significant inhibition of 20S proteasome, and actin depolimerization at later stages. Specific inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis did not prevent cell death. A short- time (6-h) exposure to DSFoxy caused a significant increase in the number of entotic cells. CONCLUSIONS: These observations indicate that MCF-7 cells treated with a mixture of DDC and B12b die by the mechanism of paraptosis. A short- time exposure to DSFoxy caused, along with paraptosis, a significant activation of the entosis and its final stage, lysosomal cell death. GENERAL SIGNIFICANCE: The results obtained open up opportunities for the development of new approaches to induce non-apoptotic death of cancer cells by dithiocarbamates.
Sujet(s)
Antinéoplasiques , Tumeurs du sein , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Tumeurs du sein/traitement médicamenteux , Disulfirame/pharmacologie , Acide diéthyl-dithiocarbamique/composition chimique , Acide diéthyl-dithiocarbamique/pharmacologie , Durée du traitement , Entose , Femelle , Humains , Cellules MCF-7RÉSUMÉ
Disulfiram (DSF) is nontoxic and exerts anticancer activity by forming highly toxic chelates via its metabolite diethyldithiocarbamate with transition metal ions. However, there are not enough such ions in the human body to maintain the therapeutic effect. Herein, we report nanogels that complex copper ions or cis-platinum (CDDP) for tumor metal delivery to potentiate DSF's antitumor efficacy. We synthesized zwitterionic poly[N-(3-(methacryloyloxy-2-hydroxy)propyl)]-N-methyl glycine (PGMA-SAR) capable of chelating copper ions or CDDP and formed nanogels with suitable size and zeta potential. The intravenously injected nanogels circulated long in the blood compartment and delivered a high concentration of metal ions to the tumor. Separately administered DSF could sequester the metal ions from the nanogels and form highly cytotoxic complexes with potent in vitro and in vivo anticancer activity. This study provides a new strategy to potentiate DSF in anticancer treatment.
Sujet(s)
Cuivre , Disulfirame , Lignée cellulaire tumorale , Cisplatine/pharmacologie , Disulfirame/pharmacologie , Acide diéthyl-dithiocarbamique/pharmacologie , Humains , NanogelsRÉSUMÉ
The effects of superoxide dismutase (SOD) inhibitors, diethyldithiocarbamate (DDC), triethylenetetramine (trien), and their combination with glucose on cells of the epidermis from pea leaves of different age (rapidly growing young leaves and slowly growing old leaves) was investigated. DDC and trien caused death of the guard cells as determined by destruction of their nuclei. Glucose did not affect destruction of the nuclei induced by SOD inhibitors in the cells from old leaves, but intensified it in the cells from young leaves. 2-Deoxyglucose, an inhibitor of glycolysis, and propyl gallate, SOD-mimic and antioxidant, suppressed destruction of the nuclei that was caused by SOD inhibitors and glucose in cells of the epidermis from the young, but not from the old leaves. Glucose and trien stimulated, and propyl gallate reduced generation of reactive oxygen species (ROS) in the pea epidermis as determined by the fluorescence of 2',7'-dichlorofluorescein (DCF). Carbonyl cyanide m-chlorophenylhydrazone (CCCP), a protonophoric uncoupler of oxidative and photosynthetic phosphorylation, suppressed the DCF fluorescence in the guard cells. Treatment of the cells with CCCP followed by its removal with washing increased destruction of the nuclei caused by SOD inhibitors and glucose. In young leaves, CCCP was less effective than in old ones. The findings demonstrate the effects of SOD inhibitors and glucose on the cell death and generation of ROS and could indicate glycolysis-dependent ROS production.
Sujet(s)
Acide diéthyl-dithiocarbamique/pharmacologie , Glucose/métabolisme , Pisum sativum/effets des médicaments et des substances chimiques , Épiderme végétal/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène , Superoxide dismutase/antagonistes et inhibiteurs , Trientine/pharmacologie , Mort cellulaire , Chélateurs/pharmacologie , Antienzymes/pharmacologie , Glucose/pharmacologie , Pisum sativum/enzymologie , Pisum sativum/métabolisme , Pisum sativum/physiologie , Épiderme végétal/enzymologie , Épiderme végétal/métabolisme , Épiderme végétal/physiologie , Feuilles de plante/effets des médicaments et des substances chimiques , Feuilles de plante/enzymologie , Feuilles de plante/métabolisme , Feuilles de plante/physiologieRÉSUMÉ
Chagas disease is caused by Trypanosoma cruzi and affects thousands of people. Drugs currently used in therapy are toxic and have therapeutic limitations. In addition, the genetic diversity of T. cruzi represents an important variable and challenge in treatment. Sodium diethyldithiocarbamate (DETC) is a compound with pharmacological versatility acting as metal chelators and ROS generation. Thus, the objective was to characterize the antiparasitic action of DETC against different strains and forms of T. cruzi and their mechanism. The different strains of T. cruzi were grown in LIT medium. To evaluate the antiparasitic activity of DETC, epimastigote and trypomastigote forms of T. cruzi were used by resazurin reduction methods and by counting. Different response patterns were obtained between the strains and an IC50 of DETC ranging from 9.44 ± 3,181 to 60.49 ± 7.62 µM. Cell cytotoxicity against 3T3 and RAW cell lines and evaluated by MTT, demonstrated that DETC in high concentration (2222.00 µM) presents low toxicity. Yet, DETC causes mitochondrial damage in T. cruzi, as well as disruption in parasite membrane. DETC has antiparasitic activity against different genotypes and forms of T. cruzi, therefore, representing a promising molecule as a drug for the treatment of Chagas disease.
Sujet(s)
Maladie de Chagas/parasitologie , Acide diéthyl-dithiocarbamique/pharmacologie , Trypanocides/pharmacologie , Trypanosoma cruzi/effets des médicaments et des substances chimiquesRÉSUMÉ
Herein, a multi-functional nanoplatform (PDA-DTC/Cu-MnO2) was established, which has been employed for MR imaging-guided multi-therapy (CDT, PTT and chemotherapy) for cancer treatment. The in vitro and in vivo results confirmed that the biocompatible nanoplatform could significantly induce tumor cell death and inhibit tumor growth.