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Disulfiram (DSF) is a conventional alcohol-aversion drug that has recently been explored as a chemotherapeutic agent and has shown excellent anticancer activity in cooperation with Cu2+ ions. However, the existing DSF delivery system has multiple shortcomings, including low drug loading and Cu2+ delivery efficiency, hindering its clinical applicability. Here, we demonstrated a simple but efficient strategy for realizing the controllable loading of hydrophobic DSF into Cu2+-doped mesoporous silica nanoparticles (Cu-MSN) by using supercritical CO 2 technology with ultra-high drug loading efficiency. Benefiting from the unique environment of high pressure and solubility, DSF was well dispersed in supercritical CO 2 and immersed into the carriers with controllable drug loading. Factorial experiments indicated an optimal condition (55 °C, 250 bar, and 6 h) for the DSF loading up to 30.8 %. In vitro and in vivo experiments demonstrated high Cu2+-enhanced chemotherapeutic efficacy of DSF. In particular, in cooperation with Cu2+ ions in MSN, the formation of complex (CuET) greatly enhanced and prolonged the antitumor effect. Together, our findings indicated that DSF-loaded Cu-MSN prepared using supercritical solvent impregnation (SSI) enhanced the antitumor effect and had potential in anticancer therapy. • The Ultra-high DSF-loaded Delivery System could be prepared by SSI. • The drug loading could be controlled by adjusting temperature, pressure. • In cooperation with Cu2+ ions in MSN, the formation of CuET greatly enhanced and prolonged the antitumor effect. [ABSTRACT FROM AUTHOR]

Summary: Drug resistance is a major problem in successful cancer chemotherapy. Many molecular mechanisms that are responsible for drug resistance are known whereas others have yet to be discovered. Determining the exact mechanism activated in a particular case (clinical or laboratory) is a difficult task. Recently, proteomics has been applied to investigate drug resistance mechanisms in model cancer cell lines. As a result, novel mechanisms of resistance have been discovered and known mechanisms of resistance confirmed. In this paper, we wish to review recent developments and progresses in the application of proteomic tools to identify known and novel drug resistance mechanisms in drug-selected model cancer cell lines. Our combined analyses of multiple proteomic studies of various drug resistant cancer cell lines revealed that many mechanisms of resistance likely exist in any given drug-selected cancer cell line and that common mechanisms of resistance may be selected in a spectrum of cancer cell lines. These observations suggest that combination therapies targeting multiple mechanisms to sensitize drug resistant cancers may be necessary to eradicate cancers in the future. [Copyright &y& Elsevier]

Abstract: One important regulation of gene expression in eukaryotes occurs at the level of mRNA translation, specifically at the step of translational initiation. Deregulation at this step will cause abnormal gene expression, leading to altered cell growth and possibly cancer. Translational initiation is controlled by multiple eIFs and one of these, eIF3, is the most complex and important factor for regulation of translation. Various subunits of eIF3 have recently been implicated to play important roles in regulating translation of specific mRNAs encoding proteins important for cell growth control. The expression of these eIF3 subunits has also been found altered in various human tumors and their altered expression may cause cancer and/or affect prognosis. Although the importance of translational regulation in cell growth control and oncogenesis is being slowly recognized, more vigorous studies on the role of eIFs in oncogenesis and cancer will likely benefit diagnosis, prognosis, and treatment of human cancers. [Copyright &y& Elsevier]

• The experimental solubility of DSF in SCF was determined in the range of 7.89 × 10−5 to 6.71 × 10-4 mole fraction. • DSF and CuET nanoparticles were successfully fabricated by the RESS process. • The dispersibility of the particles could be regulated by PVP and mPLLA-PEG. • Adjusting the PVP concentration resulted in needle-like CuET particles. • The dissolution rate and antitumor efficacy of DSF were significantly enhanced. Despite the success in exploring and repurposing of its various biological efficacies such as antitumor and others, disulfiram (DSF), a copper-dependent antitumor drug, suffers from multiple shortcomings of poor aqueous solubility and instability in the physiological environment, which often hinder its clinical applicability. Moreover, the limited availability of copper in the body also hampered the therapeutic ability of DSF. Initially, the determined experimental solubility values of DSF (7.89 × 10−5 to 6.71 × 10-4 mole fraction) in supercritical carbon dioxide (SC−CO 2) at different critical conditions are subsequently correlated using various empirical models. Further, the sub-micronized products of DSF (with mean diameters ranging from 1.53 ± 0.45 to 0.62 ± 0.11 μm) and its subsequent DSF-copper complexes (CuET) (with mean diameters ranging from 1.45 ± 0.45 to 0.27 ± 0.06 μm) are fabricated using the rapid expansion of supercritical solutions (RESS) process. Further, the suspension ability of these complexes is improved by coating with polyvinylpyrrolidone (PVP) and methoxy b -poly(L -lactide) 2000- poly(ethylene glycol) 2000 (mPLLA-PEG) solution using the RESS-based processes that with the different receiving mediums. The physicochemical properties and dissolution profiles of these composites are systematically recorded. in vitro anti-proliferation studies confirmed the substantial augmentation of bioefficacy of micronized DSF in the presence of copper. Moreover, the polymer-coated DSF or CuET nanoparticles significantly enhanced the toxicity of DSF, attributing to their relatively smaller sizes and excellent dispersibility in the aqueous environment. Thus, our findings showed that the altered dissolution rate of drugs and the synergistic effect of the metal species in CuET complex significantly amplified the antitumor efficacy of DSF, indicating the potential of RESS process in enhancing the dissolution rate as well as substantial antitumor efficiency of nano-sized drugs and their complexes. [ABSTRACT FROM AUTHOR]

Abstract Signal transducer and activator of transcription 3 (STAT3) controls many biological processes including differentiation, survival, proliferation, and angiogenesis. In normal healthy cells, STAT3 is tightly regulated to maintain a momentary active state. However, aberrant or constitutively activated STAT3 has been observed in many different cancers and constitutively activated STAT3 has been shown to associate with poor prognosis and tumor progression. For this reason, STAT3 has been studied as a possible target in the treatment of many different types of cancers. However, despite decades of research, a FDA-approved STAT3 inhibitor has yet to emerge. In this review, we will analyze past studies targeting STAT3 for drug discovery, understand possible causes of failure in these studies, and provide potential insights for future efforts to overcome these roadblocks. [ABSTRACT FROM AUTHOR]

Survivin, the smallest member of the inhibitor of apoptosis protein (IAP) family, is overexpressed in cells of almost all cancers but not in most normal tissues in adults. Survivin expression is required for cancer cell survival and knocking down its expression or inhibiting its function using molecular approaches results in spontaneous apoptosis. Thus, survivin is an attractive and perhaps ideal target for cancer drug discovery. However, a US Food and Drug Administration (FDA)-approved drug targeting survivin has yet to emerge. In this Foundation Review, we examine and evaluate various strategies that have been used to target survivin and the stages of each survivin inhibitor to help understand this lack of success. We also provide future perspectives moving forward in targeting survivin for drug discovery. [ABSTRACT FROM AUTHOR]

[Display omitted] • The novel rocket-like Janus-type CuS-ZIF-8-Dox JNPs were synthesized by a dual-solvent method. • The self-propelled CuS-ZIF-8-Dox JNPs penetrated deep tumor due to NIR-induced local thermal gradient. • Each component of CuS-ZIF-8-Dox JNPs showed specific optimal subcellular localization after cell internalization. The tumor tissue delivery of nanomaterials and the components' intracellular location are particularly critical for the effect of tumor treatment. However, the abominable conditions in the tumor microenvironment hinder nanomaterials' penetration, inducing the therapeutic action only on the surface of tumor tissue. And it is low-efficiency for therapy to spread nanomaterials in relatively expansive cytoplasm or organelles nonspecifically. Herein, we employed a near-infrared (NIR) light-induced self-propelled doxorubicin-loaded zeolitic imidazolate framework-8 capped copper sulfide Janus nanoparticles (CuS-ZIF-8-Dox JNPs) for deep tumor penetration and cancer therapy. The rocket-like Janus structure was rapidly synthesized by a dual-solvent method. Under NIR light irradiation, the rocket-like CuS-ZIF-8 JNPs showed directional wide-range motion. In addition, benefiting from the pH-responsive degradation of ZIF-8, various components were conveyed to the appropriate locations after cell internalization, i.e. , Dox targeted the nucleus, and CuS nanoparticles escaped from lysosomes to the cytoplasm. Taking advantage of the local thermal gradient under the NIR light irradiation and intracellular arrangement for different components, this Janus nanocomposite displayed a deep tumor penetration, and achieved NIR and pH dual-responsive photothermal-enhanced chemodynamic therapy and chemotherapy in vitro and in vivo. [ABSTRACT FROM AUTHOR]

[Display omitted] Survivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature. We previously attempted to target its dimerization domain with a hypothesis that inhibiting survivin dimerization would promote its degradation in proteasome, which led to identification of a lead small-molecule inhibitor, LQZ-7F. LQZ-7F consists of a flat tetracyclic aromatic core with labile hydrazone linking a 1,2,5-oxadiazole moiety. In this study, we tested the hypothesis that LQZ-7F could be developed as a prodrug because the labile hydrazone linker could be hydrolyzed, releasing the tetracyclic aromatic core. To this end, we synthesized the tetracyclic aromatic core (LQZ-7F1) using reported procedure and tested LQZ-7F1 for its biological activities. Here we show that LQZ-7F1 has a significantly improved potency with submicromolar IC 50's and induces spontaneous apoptosis in prostate cancer cells. It also more effectively inhibits survivin dimerization and induces survivin degradation in a proteasome-dependent manner than LQZ-7F. We also show that the combination of LQZ-7F1 and docetaxel have strong synergism in inhibiting prostate cancer cell survival. Together, we conclude that the hydrazone linker with the oxadiazole tail is dispensable for survivin inhibition and the survivin dimerization inhibitor, LQZ-7F, may be developed as a prodrug for prostate cancer treatment and to overcome docetaxel resistance. [ABSTRACT FROM AUTHOR]

Abstract: Human FASN is the key enzyme required for de novo synthesis of fatty acids. Up-regulated FASN expression has been reported in various human cancers and was thought to contribute to poor prognosis and recurrence of these cancers. Studies using model cell lines have indicated the role of FASN in both intrinsic and acquired drug and radiation resistance. Recent studies suggest that FASN may play an important role in regulating gene expression such as pro-apoptotic proteins and cellular processes such as DNA repair pathways, which in turn contribute to resistance to drug and radiation-induced apoptosis. In this review, we will highlight our recent progress in understanding the mechanism of FASN-induced resistance. [Copyright &y& Elsevier]

Abstract: In the present study, we investigated the spatiotemporal properties of locomotor activity after administration of CNS sedatives (pentobarbital and diazepam) and stimulants (theophylline and caffeine) in an open field test. The absolute and relative distances traveled in central or peripheral regions within 2h were analyzed. We found that both pentobarbital and diazepam increased total travel distances, especially within the initial 30min, when traveling was mainly in the peripheral region. Pentobarbital induced this hyperactivity at higher doses (maximum at 30mg/kg); while diazepam at higher doses (4 and 8mg/kg) mainly decreased the traveled distance during 0–1h but increased that in the periphery during 1–2h. On the other hand, both theophylline and caffeine generally increased the traveled distance in the central region; this effect lasted longer with increasing dose. Caffeine increased the traveled distance at lower doses (maximum at 10mg/kg) but decreased it at higher doses (30 and 100mg/kg) during the initial 1h. Theophylline exhibited a similar but smaller decrease at higher doses. Thus, we revealed the spatiotemporal properties that sedatives decrease central locomotion but induce a dose-related peripheral hyperactivity while stimulants induce central hyperactivity with a bell-shaped dose–response relation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The objective of this study was to develop a novel comonomer-free light-cured glass-ionomer system based on the 4-arm star-shape poly(acrylic acid). The mechanical strengths and in vitro cytotoxicity of the formed system were evaluated and compared with those of several representative commercial glass-ionomer cements. Materials and methods: The 4-arm poly(acrylic acid) was synthesized using ATRP and tethered with glycidyl methacrylate (GM). The GM-tethered polymer was formulated with water, photo-initiators, and Fuji II LC filler. Fuji II, Fuji II LC and Vitremer were used for comparison. Compressive strength (CS) and MTT assay were used as tools to evaluate the mechanical strengths and in vitro cytotoxicity of the cements, respectively. Results: The experimental cement exhibited significantly high compressive, diametral tensile and flexural strengths as compared to commercial glass-ionomer cements, Fuji II, Fuji II LC and Vitremer. The effects of polymer/water (P/W) ratio, GM-grafting ratio, glass powder/polymer liquid (P/L) ratio and aging in water on strengths were significant. Similar to conventional glass-ionomer cement Fuji II, the eluates from the experimental cement showed little in vitro cytotoxicity to Balb/c mouse fibroblast cells, as compared to Fuji II LC and Vitremer that contain HEMA as a comonomer. Conclusions: It appears that this novel comonomer-free light-cured glass-ionomer cement will be a promising dental restorative because it demonstrated significantly improved mechanical strengths and almost no in vitro cytotoxicity as compared to current commercial light-cured glass-ionomer cements. [Copyright &y& Elsevier]

Various conventional treatment strategies for volumetric muscle loss (VML) are often hampered by the extreme donor site morbidity, the limited availability of quality muscle flaps, and complicated, as well as invasive surgical procedures. The conventional biomaterial-based scaffolding systems carrying myoblasts have been extensively investigated towards improving the regeneration of the injured muscle tissues, as well as their injectable forms. However, the applicability of such designed systems has been restricted due to the lack of available vascular networks. Considering these facts, here we present the development of a unique set of two minimally invasively injectable modular microtissues, consisting of mouse myoblast (C2C12)-laden poly(lactic- co -glycolic acid) porous microspheres (PLGA PMs), or the micro-muscles, and human umbilical vein endothelial cell (HUVEC)-laden poly(ethylene glycol) hollow microrods (PEG HMs), or the microvessels. Besides systematic in vitro investigations, the myogenic performance of these modular composite microtissues, when co-injected, was explored in vivo using a mouse VML model, which confirmed improved in situ muscle regeneration and remolding. Together, we believe that the construction of these injectable modular microtissues and their combination for minimally invasive therapy provides a promising method for in situ tissue healing. [ABSTRACT FROM AUTHOR]

[Display omitted] Anthracycline are inhibitors of topoisomerase II leading to DNA double strand breaks, and it is widely used for treatment of breast cancer. eIF3a is the largest subunit of eukaryotic translation initiation factor 3 (eIF3) and highly expressed in breast cancer. In this study, we investigated the role of eIF3a in DSB DNA repair and the response of breast cancer patients to anthracycline-based chemotherapy. MTT assay was used to detect anthracycline sensitivity in cell lines. Real-time reverse transcriptase PCR, western blotting and immunofluorescence were performed to assess changes in gene expression levels. Cometassay and end-joining activity assay were conducted to explore the effect of eIF3a in NHEJ repair. Luciferase reporter assay was performed to detect LIG4 5′UTR activity. Immunohistochemistry was used to detect eIF3a, LIG4 and DNA-PKcs expression levels in breast cancer tissues. The results showed that eIF3a increased cellular response to anthracyclines by regulating DSB repair activity via influencing the expression of LIG4 and DNA-PKcs at translational level. Breast cancer patients with high level of eIF3a or low level of LIG4 or low level of DNA-PKcs had better anthracycline-based chemotherapy prognosis compared. Moreover, Combined expressions of eIF3a, LIG4 and DNA-PKcs could be better to predict PFS in breast cancer patients with anthracycline-based chemotherapy. Our findings suggest that eIF3a effects anthracycline-based chemotherapy response by regulating DSB DNA repair. [ABSTRACT FROM AUTHOR]