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Because of the extremely complexed microenvironment of drug-resistant bacterial infection, nanomaterials with both bactericidal and immuno-modulating activities are undoubtedly the ideal modality for overcoming drug resistance. Herein, we precisely engineered the surface chemistry of selenium nanoparticles (SeNPs) using neutral (polyvinylpyrrolidone-PVP), anionic (letinan-LET) and cationic (chitosan-CS) surfactants. It was found that surface chemistry greatly influenced the bioactivities of functionalized SeNPs, their interactions with methicillin-resistant Staphylococcus aureus (MRSA), immune cells and metabolisms. LET-functionalized SeNPs with distinct metabolisms exhibited the best inhibitory efficacy compared to other kinds of SeNPs against MRSA through inducing robust ROS generation and damaging bacterial cell wall. Meanwhile, only LET-SeNPs could effectively activate natural kill (NK) cells, and enhance the phagocytic capability of macrophages and its killing activity against bacteria. Furthermore, in vivo studies suggested that LET-SeNPs treatment highly effectively combated MRSA infection and promoted wound healing by triggering much more mouse NK cells, CD8+ and CD4+ T lymphocytes infiltrating into the infected area at the early stage to efficiently eliminate MRSA in the mouse model. This study demonstrates that the novel functionalized SeNP with dual functions could serve as an effective antibacterial agent and could guide the development of next generation antibacterial agents. [ABSTRACT FROM AUTHOR]

The detection, analysis and clearing of circulating tumor cells (CTCs) from patients' bloodstream at an early stage are important to diagnose the primary tumor progression and decrease cancer metastasis-related mortality. Herein, we developed a molybdenum diselenide nanosheet (MoSe 2 NS) based magnetic nanosystem, which was surface functionalized with the anti-epithelial cell adhesion molecule (anti-EpCAM) antibody. CTCs were successfully isolated by the magnetic nanosystem from blood samples of clinical cancer patients. Highly efficient CTCs enrichment was achieved when the nanosystem was applied with a concentration down to 25 µg ml−1 in both static and biomimetic circulating conditions. The nanosystem was demonstrated biocompatible without obvious cytotoxicity, allowing in vitro culture of the captured cells for downstream analysis. Further, the magnetic nanosystem presented a reinforced photothermal effect due to the integration of several photothermal agents including MoSe 2 NS, ferroferric oxide (Fe 3 O 4) nanoparticles, and polydopamine (pDA), allowing fast in-situ elimination of the captured cells under NIR laser (808 nm) irradiation. This work represents a multimode system that enables highly efficient enrichment of rare CTCs from patients' blood for either retrieval or clearing, with great promise for early cancer diagnosis and possible treatment screening. [Display omitted] • MoSe 2 nanosheets-based magnetic nanosystem that efficiently enriches rare CTCs from cancer patients' blood is constructed. • The system can work as a multimode cancer diagnosis and treatment platform for CTCs retrieval and in situ elimination. • This study shows promise for developing next generation CTCs enrichment nanosystem against tumor metastasis and recurrence. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating condition with limited efficacious treatment options. Recent research has revealed the potential of functional nanomedicines to inhibit ferroptosis and reduce inflammatory response, offering a promising therapeutic approach for SCI. Urolithin A (UA) exhibits outstanding antioxidant and anti-inflammatory properties in different neurodegenerative disorders. Intriguingly, whether UA can antagonize ferroptosis remains unknown, and its specific impact on SCI and underlying mechanisms have not been extensively explored. Given the pathological response of esterase overexpression in the SCI microenvironment, taken advantages of nanotechnology in precise targeted delivery, flexible structure design and effective enhancement of drug metabolism pathways, in this study, a novel silica-based integrated nanocarrier is constructed by incorporating carbamate-bridged UA into silica nanoparticles. The resulting PEGylated UA silicon hybrid NPs (PUASi NPs) are sensitive and could be specifically recognized and cleaved by esterase. The findings from both in vitro and in vivo experiments demonstrate that the continuous release of UA from PUASi NPs exhibits notable anti-ferroptotic and anti-inflammatory effects, thus contributing to the improvement of functional recovery in mice suffering from SCI. Collectively, this esterase-activatable nanoprodrug strategy offers an alternative therapeutic regimen for clinical intervention in SCI, with promising prospects for translation into clinical practice. [Display omitted] • PUASi NPs are sensitive and could be specifically recognized and cleaved by esterase. • The sustained release of UA not only inhibit ferroptosis but also protect neuronal cells from neuroinflammatory damage. • PUASi NPs promote nerve regeneration after SCI via reducing ferroptosis and reprogramming inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged Cu 2−x Se nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, Cu 2−x Se had the ability to scavenge glutathione (GSH) and produce ·OH with excess H 2 O 2 in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the 1O 2 produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged Cu 2−x Se nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment. [Display omitted] • DR5 overexpression enables CCMT with Cu 2−x Se/TRAIL-camouflaged membrane. • TRAIL-CCMT excels in targeting, immune evasion, and radiosensitization via GSH depletion and metabolic disruption. • CCMT proves superior against cervical cancer radioresistance. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) possesses high mortality rate and becomes the third most common cause of cancer death. Searching new therapeutic strategies for HCC are still urgently needed. In situ thermosensitive hydrogels loading with chemotherapeutics have attracted increasing attention for HCC due to their superior advantages including high drug loading and sustained drug release behavior. Herein, we developed a novel in situ injection thermosensitive hydrogel system based on Poloxamer 407 (P407) and selenium nanoparticle loading with DOX (PPS-SeNPs@DOX) for localized synergistic chemoradiotherapy of HCC. The synthesized PPS-SeNPs@DOX hydrogel system showed a better phase transition temperature at 32 ℃, and the mechanical properties were not affected under X-ray irradiation, which suggests the stability of the synthesized hydrogel. The localized injection of PPS-SeNPs@DOX combined with radiotherapy was found to significantly suppress HepG2 tumors growth in vivo , as evidenced by the decreased tumor volume, tumor weight and Ki67 expression. Furthermore, the synergistic anticancer effects in orthotopic Hepa1-6 tumors were also found in the combination treatment of PPS-SeNPs@DOX and X-ray irradiation with the involvement of antitumor immunity activation accompanied by the upregulated population of CD8+ T, M1 and NK1.1 cells and downregulated population of Gr1 cells after single in situ injection. Taken together, this study presents a novel in situ injection thermosensitive hydrogel system for the chemoradiotherapy of HCC, which may provide a solid foundation for designing local delivery platform for unresectable HCC therapy. [Display omitted] • PPS-SeNPs@DOX thermosensitive hydrogel with an appropriate Tt was designed for the local continuous treatment of HCC. • PPS-SeNPs@DOX significantly prolongs the release time of SeNPs and DOX in local site. • Combination of localized chemoradiotherapy significantly inhibited the growth of HCC and regulated the antitumor immunity. [ABSTRACT FROM AUTHOR]

Tolerance to radiotherapy is the main cause of radiotherapy failure in patients with lung cancer. The key to successful treatment is to find effective targets and signaling pathways to reverse radioresistance. Based on the importance of the epidermal growth factor receptor (EGFR) signaling pathway and mitochondria in lung cancer, we developed an EGFR/mitochondrial dual-targeting radiosensitizer (M-TeNSs@Ge-11) based on tellurium nanostars to overcome radioresistance in lung cancer. The as-prepared M-TeNSs@Ge-11 nanosystem successfully located in the mitochondria not only increased the accumulation and penetration of the Te nanosystem in radiotherapy-tolerant lung cancer cells but also enhanced the sensitivity of A549 cells to X-rays, leading to excellent anticancer efficacy via overproduction of reactive oxygen species and mitochondrial dysfunction. Consistently, using unilateral and bilateral tumor models, we confirmed that M-TeNSs@Ge-11 combined with X-ray irradiation had a high therapeutic effect and could reshape the tumor immune microenvironment by affecting the infiltration of some specific immune cells, such as M2 macrophages and natural killer cells. Taken together, our study highlights a facile design strategy for Te-based nanoradiosensitizers to reverse the radiation resistance of lung cancer. Furthermore, the findings provide novel insights into their application in theranostics in cancer medicine. [Display omitted] • EGFR and mitochondria dual targeted M-TeNSs@Ge-11 exhibits high accumulation and penetration in tumor cells and tissues. • M-TeNSs@Ge-11 possesses excellent ability to reverse the radiotherapy-tolerant lung cancer. • M-TeNSs@Ge-11 in combination of radiotherapy exerts stronger antitumor efficacy in multiple mouse tumor models. • This strategy can effectively induce robust immunities through remodeling tumor microenvironment. [ABSTRACT FROM AUTHOR]

Angiogenesis is essential for tumorigenesis, progression and metastasis. Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) targeting tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. After internalization by receptor-mediated endocytosis, this nanosystem disassembled under acidic condition with the presence of lysozymes and cell lysate, leading to bioresponsive triggered drug release. Mechanistic investigation revealed that RGD-NPs inhibited angiogenesis through induction of apoptosis and cell cycle arrest in human umbilical vein endothelial cells (HUVECs) via suppression of VEGF-VEGFR2-ERK/AKT signaling axis by triggering ROS-mediated DNA damage. Additionally, RGD-NPs can inhibit MCF-7 tumor growth and angiogenesis in nude mice via down-regulation of VEGF-VEGFR2, effectively reduce the toxicity and prolong the blood circulation in vivo. Our results suggest that the strategy to use RGD-peptide functionalized SeNPs as carriers of anticancer drugs is an efficient way to achieve cancer-targeted antiangiogenesis synergism. [ABSTRACT FROM AUTHOR]

Radioresistance has been the main obstacle of cervical cancer radiotherapy. Hence, it's urgent need to develop effective radiosensitizers for improving the radiotherapeutic efficacy. MoSe 2 has been recognized as a promising therapeutic nanoplatform in radio/photo-mediated cancer therapy, due to its narrow bandgap and good photoelectric/photothermal conversion capabilities, while these physical properties and its biological performance can be various depending on its structure. Herein, radiosensitization nanosystems based on two common forms of MoSe 2 nanomaterial, 2D nanosheet (NS) and 3D nanoflower (NF), were developed, and their therapeutic efficacy and mechanisms in treating cervical cancer were contrastively analyzed. In vitro experiments on Hela and Siha cells demonstrated superior synergistic therapeutic efficacy of MoSe 2 NF-RGD over MoSe 2 NS-RGD. Further analysis revealed that compared to MoSe 2 NS-RGD, MoSe 2 NF-RGD efficiently targeted and accumulated in cancer cell mitochondria, leading to mitochondria-mediated apoptosis associated with p53 phosphorylation. Moreover, the metabolites of MoSe 2 NF-RGD including selenocystine (SeCys 2) and methylselenocysteine (MeSeCys 2) also contributed to its unique advantages in radiosensitized cancer-killing effect. Consistently, in vivo study confirmed higher therapeutic efficacies of MoSe 2 NF-RGD combined with X-ray against the primary tumor as well as distant tumor through boosting the infiltration of some specific immune cells including dendritic cells (DCs) and NK1.1 cells. Collectively, this work revealed the influence of material structure on the biological performance and radiotherapeutic efficacy of MoSe 2 -based nanosystems and the underlying mechanisms for these structure-dependent difference. Morphology-directed MoSe 2 nanosystems could regulate selenoproteins and promote DNA damage to enhance X-ray radiotherapy. The MoSe 2 nanoflower regulates TrxR2 expression through metabolism into SeCys 2 and MeSeCys 2 and induces ROS-mediated apoptosis and cell cycle arrest by triggering mitochondrial dysfunction. [Display omitted] • Nanoflower-shaped MoSe 2 can absorb more photon energy with stronger radiocatalytic ability. • MoSe 2 NF-RGD exerts superior synergistic radiotherapeutic efficacy. • Different morphology determines the mitochondrial accumulation of MoSe 2 nanosystems. • Metabolism into SeCys 2 and MeSeCys 2 contributes to stronger radiosensitization of MoSe 2 NF-RGD. • MoSe 2 NF-RGD exhibits stronger antitumor efficacy through boosting immune response. [ABSTRACT FROM AUTHOR]

This study was to investigate whether natural borneol (NB) could enhance the anti-cancer effect of demethoxycurcumin (DCur) on HepG2 cell line by MTT assay, flow cytometry, and western blotting assay. Our results demonstrated that NB/DCur resulted in a significant decrease in cell viability due to pretreatment of NB enhancing the cellular uptake of DCur. Flow cytometric assay showed that NB/DCur-induced HepG2 cells growth inhibition was mainly caused by induction of G2/M arrest, as evidenced by accumulation of the G2/M cell population. Immunoblotting assay demonstrated that NB/DCur down-regulated expression levels of cdc2 and cyclin B1, which contributed to G2/M arrest. Moreover, NB/DCur elevated the level of intracellular reactive oxygen species (ROS), indicating that NB/DCur-induced G2/M arrest was achieved by triggered ROS-mediated DNA damage involving MAPK and Akt signaling pathways. Taken together, our results suggested that the combination of NB and DCur induced G2/M phase arrest in HepG2 through ROS overproduction. This study demonstrated that NB had the potential to be further developed into a chemosensitizer of DCur in the treatment of human cancers. [ABSTRACT FROM AUTHOR]

Multidrug resistance is one of the greatest challenges in cancer therapy. Herein we described the synthesis of folate (FA)-conjugated selenium nanoparticles (SeNPs) as cancer-targeted nano-drug delivery system for ruthenium polypyridyl (RuPOP) exhibits strong fluorescence, which allows the direct imaging of the cellular trafficking of the nanosystem. This nanosystem could effectively antagonize against multidrug resistance in liver cancer. FA surface conjugation significantly enhanced the cellular uptake of SeNPs by FA receptor-mediated endocytosis through nystain-dependent lipid raft-mediated and clathrin-mediated pathways. The nanomaterials overcame the multidrug resistance in R-HepG2 cells through inhibition of ABC family proteins expression. Internalized nanoparticles triggered ROS overproduction and induced apoptosis by activating p53 and MAPKs pathways. Moreover, FA-SeNPs exhibited low in vivo acute toxicity, which verified the safety and application potential of FA-SeNPs as nanodrugs. This study provides an effective strategy for the design of cancer-targeted nanodrugs against multidrug resistant cancers. From the Clinical Editor In the combat against hepatocellular carcinoma, multidrug resistance remains one of the obstacles to be overcome. The authors designed and synthesized folate (FA)-conjugated selenium nanoparticles (SeNPs) with enhanced cancer-targeting capability. This system carried ruthenium polypyridyl (RuPOP), an efficient metal-based anti-cancer drug with strong fluorescence. It was shown that this combination was effective in antagonizing against multidrug resistance in vitro. [ABSTRACT FROM AUTHOR]

• MSeNP@CIP targets macrophages to treat atherosclerosis. • MSeNP@CIP reduces aortic plaques by protecting ATP-binding cassette transporter against calpain proteolytic cleavage. • MSeNP@CIP can reprogram macrophages to an M2 phenotype to exert anti-inflammatory effects. [Display omitted] Nanoparticles utilizing the D -mannose along with potent anti-inflammatory selenium and CIP (MSeNP@CIP) were synthesized as highly stabile, biocompatible therapeutic reagents targeting to the atherosclerotic lesion. MSeNP@CIP is capable of protecting the key regulators of cholesterol homeostasis ABCA1 against calpain by inhibiting the calpain activity, and ameliorated the foam cells formation substantially. It was also shown to upregulate the proportion of M2 phenotype macrophages thus exhibits anti-inflammatory effect. The present study provides a strategy for functionalization of nanomedicines using structure-optimized SeNP, and mechanistic insight for the precise treatment of atherosclerosis. Atherosclerosis is a leading cause of death worldwide as characterized by the accumulation of lipid-overloaded macrophages exhibiting high expression of mannose receptors (MRs) in the arterial wall. Hyperactivation of the calpain proteolytic system has been reported to contribute to the progression of atherosclerosis through cleavage of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in macrophages. However, the efficiency and specificity of conventional calpain inhibitors are substantially limited, reducing their capacity to influence calpain mediated pathology. To address this issue, a translational nanosystem was developed using immune enhancing selenium in the form of D -mannose modified selenium nanoparticle (MSeNP) loaded with calpain inhibitory peptide (CIP) (MSeNP@CIP). The D -mannose modification enhanced accumulation of MSeNP@CIP in the atherosclerotic plaques by specifically binding to mannose receptors, thus reducing plaque formation via inhibition of calpain activity, leading to lower levels of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Moreover, by regulating the ratio of M1/M2 macrophages, MSeNP@CIP exhibits strong anti-inflammatory effects. Taken together, this study provides the framework for a targeted nanotherapy to mitigate atherogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Cyanidin is an anthocyanin widely distributed in food diet with novel antioxidant activity. Herein, we investigated the protective effects of cyanidin on HK-2 proximal tubular cells against cisplatin-induced apoptosis and elucidated the underlying mechanisms. The results showed that cisplatin-induced apoptosis in HK-2 cells was significantly attenuated by cyanidin. The cleavage of caspases and PARP, activation of p53 and mitochondrial-mediated apoptosis pathways induced by cisplatin were effectively blocked by cyanidin. Moreover, cyanidin significantly suppressed the overproduction of ROS, and activation of ERK and AKT pathways triggered by cisplatin. Our results indicate that cyanidin exhibits therapeutic potential in prevention of cisplatin-induced nephrotoxicity. [Copyright &y& Elsevier]

Abstract: A simple method for preparation of adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles (SeNPs@ATP) with enhanced cell permeabilization and anticancer activity has been demonstrated in the study reported in this article. Spherical SeNPs were decorated with ATP by strong adsorption through an Se-N bond, leading to the highly stable structure of the conjugates. ATP surface decoration significantly enhanced the cellular uptake and anticancer activity of SeNPs. Induction of apoptosis in HepG2 human hepatocellular carcinoma cells by SeNPs@ATP was evidenced by accumulation of the sub-G1 cell population, phosphatidylserine exposure, DNA fragmentation, PARP cleavage and caspase activation. Further studies found that SeNPs@ATP treatment triggered the depletion of mitochondrial membrane potential and reactive oxygen species (ROS) overproduction. Our results demonstrate that the use of ATP as a surface decorator of SeNPs is a novel strategy to achieve anticancer synergy. SeNPs@ATP may be a candidate for further evaluation as a chemotherapeutic agent for human cancers. From the Clinical Editor: In this paper, adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles are discussed as cell-penetrating anticancer agents. Conjugates are stable and ATP functionalization greatly enhances the apoptosis induction properties of the selenium nanoparticles in HepG2 human hepatocellular carcinoma cells. [Copyright &y& Elsevier]

Abstract: Misfolded human islet amyloid polypeptide (hIAPP) in pancreatic islets is associated with the loss of insulin-secreting beta cells in type 2 diabetes. Insulin secretion impairment and cell apoptosis can be due to mitochondrial dysfunction in pancreatic beta cells. Currently, there is little information about the effect of hIAPP on mitochondrial function. In this study, we used INS-1E rat insulinoma beta cells as a model to investigate the role of mitochondria in hIAPP-induced apoptosis and the protective effects of phycocyanin (PC). We demonstrated that hIAPP induced apoptosis in INS-1E cells was associated with the disruption of mitochondrial function, as evidenced by ATP depletion, mitochondrial mass reduction, mitochondrial fragmentation and loss of mitochondrial membrane potential (ΔΨ m). Further molecular analysis showed that hIAPP induced changes in the expression of Bcl-2 family members, release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytosol, activation of caspases and cleavage of poly (ADP-ribose) polymerase. Interestingly, the hIAPP-induced mitochondrial dysfunction in INS-1E cells was effectively restored by co-treatment of PC. Moreover, there was crosstalk between the extrinsic and intrinsic apoptotic pathways as demonstrated by cleavage of Bid by caspase-8 in the apoptotic process triggered by hIAPP. Taken together, we demonstrated for the first time the involvement of mitochondrial dysfunction in hIAPP-induced INS-1E cell apoptosis. Attenuation of mitochondrial dysfunction provides a mechanism for the protective effects of PC. [Copyright &y& Elsevier]

Abstract: A simple and solution-phase approach for large-scale synthesis of selenium nanoparticles (Nano-Se) by reducing sodium selenite (Na2SeO3) with l-cysteine has been demonstrated in this study. l-cysteine was used as both the reducing agent and surface modifier to control the formation of Nano-Se. The effects of reactant concentrations and ratios, and reaction time on the size and stability of Nano-Se were also investigated. The morphology and chemical composition of Nano-Se were characterized using various spectroscopic and microscopic methods. The results showed that varying the concentration ratio of l-cysteine to Na2SeO3 could control the diameter and morphology of Nano-Se, but not affecting their crystalline phases and chemical compositions. Monodisperse and homogeneous spherical Nano-Se with an average diameter of about 100nm could be synthesized with the concentration ratio of l-cysteine to Na2SeO3 at 4:1. A striking feature of the as-synthesized Nano-Se was their good stability when dispersed in the reaction solutions, which indicates their potential in medical applications. [Copyright &y& Elsevier]

Abstract: The interactions of a ruthenium porphyrin complex [(Py-3′)TPP-Ru(phen)2Cl]Cl (phen=1,10-phenanthroline, (Py-3′)TPP=5-(3′-pyridyl-10,15,20-triphenylporphyrin) (1) and its heterometallic derivatives, [Ni(Py-3′)TPP-Ru(phen)2Cl][PF6] (2) and [Cu(Py-3′)TPP-Ru(phen)2Cl][PF6] (3), with calf thymus DNA have been investigated by spectroscopic and viscosity measurements in this study. The results showed that these synthetic complexes can bind to double strand helix DNA in groove binding mode, and the intrinsic binding constants of complexes 1, 2 and 3, as calculated according to the decay of the Soret absorption, are (1.35±0.5) ×105 M−1 (s =4.2), (1.29±0.5)×105 M−1 (s =5.6) and (1.22±0.5)×105 M−1 (s =6.2) (s is the binding-site size), respectively, which are consistent with those obtained from ethidium bromide-quenching experiments. Further investigations on the photocleavage properties of these complexes on plasmid pBR 322 DNA showed that complexes 1, 2 and 3 could cleave single chain DNA and convert DNA molecules from supercoiled form to the nicked form. As determined by MTT assay, the complexes were also identified as potent antiproliferative agents against A375 human melanoma cells, MCF-7 human breast adrenocarcinoma cells, Colo201 human colon adenocarcinoma cells and HepG2 human liver cancer cells. Complex 1 inhibits the growth of A375 cells through induction of apoptotic cell death and G0/G1 cell cycle arrest. Further investigation on intracellular mechanisms indicated that Complex 1 induced depletion of mitochondrial membrane potential (ΔΨ m) in A375 cells through regulating the expression of pro-survival and pro-apoptotic Bcl-2 family members. Our results suggest that ruthenium porphyrin complexes could be candidates for further evaluation as chemopreventive and chemotherapeutic agents for human cancers. [Copyright &y& Elsevier]

Abstract: Selenadiazole derivative is one kind of synthetic organoselenium compounds with potent and broad-spectrum antitumor activity. In this study, we showed that anthrax [1,2-c] [1,2,5] selenadiazolo-6,11-dione (ASDO), an novel selenadiazole derivative, induced time- and dose-dependent apoptotic cell death in MCF-7 human breast carcinoma cells, as indicated by accumulation of sub-G1 cell population, DNA fragmentation, nuclear condensation, caspase activation and PARP cleavage. ASDO-induced apoptosis was significantly inhibited by a general caspase inhibitor z-VAD-fmk, demonstrating the important role of caspases in ASDO-induced apoptotic pathway. Treatment of MCF-7 cells with ASDO resulted in a rapid depletion of mitochondrial membrane potential and release of cytochrome c and Smac/Diablo through up-regulation of Bax, Bad and PUMA expression and down-regulation of Bcl-xl expression. Moreover, ASDO treatment up-regulated the expression levels of total p53 and its target gene p21Waf1. Silencing of p53 activation with RNA interference effectively blocked the ASDO-induced cell PARP cleavage, DNA fragmentation and caspase activation. Furthermore, ASDO-induced apoptosis was interestingly found to be independent of reactive oxygen species production. Taken together, we conclude that ASDO induces MCF-7 cell apoptosis through a p53-dependent and mitochondria-mediated pathway. [Copyright &y& Elsevier]

Abstract: The role of selenium as potential cancer chemopreventive and chemotherapeutic agents has been supported by epidemiological, preclinical and clinical studies. Although cell apoptosis has been evidenced as a critical mechanism mediating the anticancer activity of selenium, the underlying molecular mechanisms remain elusive. In the present study, we showed that selenocystine (SeC), a naturally occurring selenoamino acid, induced caspase-independent apoptosis in MCF-7 breast carcinoma cells, which was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage, caspase activation, DNA fragmentation, phosphatidylserine exposure and nuclear condensation. Moreover, SeC induced the loss of mitochondrial membrane potential (ΔΨ m) by regulating the expression and phosphorylation of Bcl-2 family members. Loss of ΔΨ m led to the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF) which subsequently translocated into the nucleus and induced chromatin condensation and DNA fragmentation. MCF-7 cells exposed to SeC shown increase in total p53 and phosphorylated p53 on serine residues of Ser15, Ser20, and Ser392 prior to mitochondrial dysfunction. Silencing and attenuating of p53 activation with RNA interference and pifithrin-α treatment, respectively, partially suppressed SeC-induced cell apoptosis. Furthermore, generation of reactive oxygen species and subsequent induction of DNA strand breaks were found to be upstream cellular events induced by SeC. The thiol-reducing antioxidants, N-acetylcysteine and glutathione, completely blocked the occurrence of cell apoptosis. Taken together, these results suggest that SeC, as a promising anticancer selenocompound, induces MCF-7 cell apoptosis by activating ROS-mediated mitochondrial pathway and p53 phosphorylation. [Copyright &y& Elsevier]