MW-19, a dihydropyrazole derivative, induces human triple-negative breast cancer cell apoptosis by targeting apoptosis-related pathways.

Previous studies have indicated that heterocyclic substituted dihydropyrazole derivatives, particularly MW-19, potentially exert anticancer activity in vitro; however, the underlying mechanism remains unknown. The present study was designed to investigate the mechanisms underlying MW-19 activity in triple-negative breast cancer cells. A sulforhodamine B assay was performed to evaluate cell proliferation inhibition rates, and the antitumor effect of MW-19 was evaluated in mice with HCC-1806 xenografts. Apoptosis was analyzed by Hoechst 33342 and annexin V/propidium iodide staining. Expression of pro- and antiapoptotic proteins and mRNA were analyzed by western blotting and reverse transcription-quantitative (RT-q) PCR, respectively. We found that MW-19 significantly inhibited HCC-1806 cell proliferation in a dose- and time-dependent manner, and significantly inhibited MDA-MB-231 cell migration. Importantly, oral administration of MW-19 significantly inhibited HCC-1806 tumor growth in BALB/c-nu/nu mice. Moreover, MW-19 treatment induced marked apoptosis and G2/M arrest in the sensitive cell line, HCC-1806. RT-qPCR analysis showed that levels of proapoptotic genes (Bax, caspase-3, caspase-7, and Fas) were considerably increased in the MW-19 group relative to the control group, while those of antiapoptotic factors (Bcl-2, C-MYC) were dramatically decreased. Consistently, Bax, caspase-3, and caspase-7 were significantly induced after MW-19 treatment, while levels of phosphorylated (p-)AKT, p-PI3K, p-ERK, and the antiapoptotic protein, Bcl-2, were clearly diminished, and the P38 MAPK signaling pathway was activated. Furthermore, P38 pharmacological inhibitors abrogated MW-19-induced apoptosis. Together, our findings indicate that MW-19 exerts antitumor effects by targeting PI3K/AKT and ERK/P38 signaling pathways.

A Room-Temperature Strategy to Synthesize Ce/Tb-Codoped NaYF4 Nanoparticles with a Photoluminescence Quantum Yield Exceeding 50.

NaYF4:Ce3+,Tb3+ down-conversion nanoparticles with a photoluminescence quantum yield (PLQY) of 54.8% are synthesized by using a ligand-assisted coprecipitation method in this study. The reaction is completed within 1 min at room temperature, and short-chain hexanoic acid and hexylamine serve as the binary ligands, which enable us to synthesize highly luminescent NaYF4:Ce3+,Tb3+ nanoparticles at room temperature. X-ray diffraction (XRD) and transmission electron microscopy (TEM) are used to characterize the as-prepared nanocrystals. The results reveal that the NaYF4:Ce3+,Tb3+ nanocrystals exhibit excellent dispersion and have a particle size of 2.7 nm. Our NaYF4:Ce3+,Tb3+ nanocrystals possess the advantages of room-temperature preparation, high PLQY, and ultrasmall particle size. These results reveal that the NaYF4:Ce3+,Tb3+ nanocrystals might have a high potential in the applications of lighting, display devices, and bioimaging.

Low-temperature in situ preparation of Eu3+/Tb3+-doped CaMoO4/SrMoO4 nanoparticle thin films and their application in anti-counterfeiting.

Rare earth-doped metal oxide thin films exhibit remarkable potential for application in anti-counterfeiting, owing to their exceptional fluorescent properties. However, the existing fabrication techniques for these rare earth-doped luminescent thin films are predominantly complex and necessitate high-temperature conditions. In light of this issue, we present a low-temperature method for in situ fabrication of luminescent Ca1-xMoO4:Eux3+ and Sr1-xMoO4:Tbx3+ nanocrystal thin films by a solution deposition process. The developed method has the advantages of simple operation, rapid and low-temperature synthesis. The optimal chemical compositions of molybdate-based luminescent films are Ca0.90MoO4:Eu0.103+ and Sr0.90MoO4:Tb0.103+. Moreover, we evaluate the practical feasibility of luminescent nanoparticle films in the field of anti-counterfeiting by combining the unique fluorescent properties of rare earth ions and designing customized fluorescent patterns.

An Ultrafast and Room-Temperature Strategy for Kilogram-Scale Synthesis of Sub-5 nm Eu3+ -doped CaMO4 Nanocrystals with a Photoluminescence Quantum Yield Exceeding 85.

Rare earth-doped metal oxide nanocrystals have a high potential in display, lighting, and bio-imaging, owing to their excellent emission efficiency, superior chemical, and thermal stability. However, the photoluminescence quantum yields (PLQYs) of rare earth-doped metal oxide nanocrystals have been reported to be much lower than those of the corresponding bulk phosphors, group II-VI, and halide-based perovskite quantum dots because of their poor crystallinity and high-concentration surface defects. Here, an ultrafast and room-temperature strategy for the kilogram-scale synthesis of sub-5 nm Eu3+ -doped CaMoO4 nanocrystals is presented, and this reaction can be finished in 1 min under ambient conditions. The absolute PLQYs for sub-5 nm Eu3+ -doped CaMoO4 nanocrystals can reach over 85%, which are comparable to those of the corresponding bulk phosphors prepared by the high-temperature solid state reaction. Moreover, the as-produced nanocrystals exhibit a superior thermal stability and their emission intensity unexpectedly increases after sintering at 600 °C for 2 h in air. 1.9 kg of Eu3+ -doped CaMoO4 nanocrystals with a PLQY of 85.1% can be obtained in single reaction.

Room-temperature and ultrafast Eu3+ ion doping for highly luminescent and extremely small CaMoO4 nanocrystals.

We developed a room-temperature and ultrafast Eu3+-ion doping approach for the synthesis of highly luminescent Eu-doped CaMoO4 nanoparticles. Firstly, CaMoO4 nanoparticles with a particle size of 3.9 nm are rapidly prepared using a room temperature co-precipitation approach. Subsequently, Eu-doped CaMoO4 nanoparticles with a photoluminescence quantum yield of up to 75% are synthesized by a post-cation exchange reaction at room temperature. This facile and room-temperature synthetic strategy enables us to prepare highly luminescent and extremely small rare earth ion-doped metal oxide nanocrystals.

Ionic Liquid-Assisted Ink for Inkjet-Printed Indium Tin Oxide Transparent and Conductive Thin Films.

Drop-on-demand inkjet printing is used to deposit indium tin oxide (ITO) transparent and conductive thin films. ITO printable ink is prepared by dissolving indium hydroxide and tin (IV) chloride into ethanol with the assistance of acetic acid/tert-butylamine ionic liquid. Ionic liquid-assisted ITO ink exhibits a complete wetting behavior on the glass substrate and a tunable viscosity, which makes it particularly suitable for the inkjet printing fabrication of ITO thin films. After annealing at 500 °C in forming gas, ITO thin films with a sheet resistance of 99 Ω/□, a resistivity of 2.28 × 10-3 Ω·cm, and a transmittance of 95.2% in the range of 400-1000 nm can be obtained. The effects of annealing temperature on the resistivity, mobility, carrier concentration, transmittance, and optical band gap are investigated systematically. Compared with commercial ITO thin films made by conventional vacuum-based deposition approaches, these printable ITO thin films have a higher material utilization.

Room-Temperature, Ultrafast, and Aqueous-Phase Synthesis of Ultrasmall LaPO4:Ce3+, Tb3+ Nanoparticles with a Photoluminescence Quantum Yield of 74.

LaPO4:Ce3+, Tb3+ nanoparticles with a particle size of 2.7 nm are prepared by a facile room-temperature ligand-assisted coprecipitation method in an aqueous solution. Short-chain butyric acid and butylamine are used as binary ligands and play a critically important role in the synthesis of highly luminescent LaPO4:Ce3+, Tb3+ nanoparticles. The absolute photoluminescence quantum yield as high as 74% can be achieved for extremely small LaPO4:Ce3+, Tb3+ nanoparticles with an optimal composition of La0.4PO4:Ce0.13+, Tb0.53+, which is different from La0.4PO4:Ce0.453+, Tb0.153+ for bulk phosphor. The energy transfer from Ce3+ ions to Tb3+ ions is investigated in sub-3 nm LaPO4:Ce3+, Tb3+ nanoparticles, and Ce3+ ion emission is almost completely suppressed. This room-temperature, ultrafast, and aqueous-phase synthetic strategy is particularly suitable for the large-scale preparation of highly luminescent LaPO4:Ce3+, Tb3+ nanoparticles. LaPO4:Ce3+, Tb3+ nanoparticles (110 g) can be synthesized in one batch, which is perfectly suited to the needs of industrial production.

Polyphyllin I, a lethal partner of Palbociclib, suppresses non-small cell lung cancer through activation of p21/CDK2/Rb pathway in vitro and in vivo.

Cyclin-dependent kinases (CDKs) are hyperactive in many cancers and have served as cancer therapeutic targets for decades. Palbociclib (Palb) is the first approved CDK4/6 inhibitor to treat hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Acquired drug resistance is one obstacle of Palb be utilized in other cancer. CDK2 compensation of CDK4/6 loss is one of the causes that cancer cells are resistant to Palb. Hence, targeting multiple CDKs could be a novel strategy to prevent the drug resistance of cancer cells and expand the application of Palb in other cancer. In this study, we initially indicated Polyphyllin I (PPI) significantly inhibits non-small lung cancer cell (NSCLC) proliferation, promotes cell apoptosis in vitro and in vivo. Mechanistically, PPI can inhibit Rb through the p21/CDK2/Rb signaling pathway in NSCLC. A combination of PPI and Palb exerts a significant synergistic anti-cancer ability on NSCLC. Of note, PPI can reverse Palb drug resistance. Herein, we first time demonstrated PPI can disturb CDK2 function through upregulation of p21. The PPI effect on CDK2 provides a choice for a chemotherapeutic strategy for the elimination of NSCLC. Our study highlighted the clinical significance of simultaneously blocking of CDK2 and CDK4/6 for NSCLC treatment.

Discovery of a New CDK4/6 and PI3K/AKT Multiple Kinase Inhibitor Aminoquinol for the Treatment of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a lethal malignancy lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6) and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and are promising therapeutic targets for HCC. Here we identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC. Methods: Using a repurposing and ensemble docking methodology, we screened a library of worldwide approved drugs to identify candidate CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we investigated the effects of candidate drug in reducing cell-viability,inducing apoptosis, and causing cell-cycle arrest. The drug combination and thermal proteomic profiling (TPP) method were used to investigate whether the candidate drug produced antagonistic effect. The in vivo anti-cancer effect was performed in BALB/C nude mice subcutaneously xenografted with Huh7 cells. Results: We demonstrated for the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6 and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell viability, induced apoptosis, increased the percentage of cells in G1 phase. Drug combination screening indicated that aminoquinol could produce antagonistic effect with the PI3K inhibitor LY294002. TPP analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6, PI3K and AKT proteins. Finally, in vivo study in Huh7 cells xenografted nude mice demonstrated that aminoquinol exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil with the combination treatment showed the highest therapeutic effect. Conclusion: The present study indicates for the first time the discovery of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It could be used alone or as a combination therapeutic strategy for the treatment of HCC.

A multicenter, randomized controlled trial of massage in children with pediatric cerebral palsy: Efficacy of pediatric massage for children with spastic cerebral palsy.

BACKGROUND: Cerebral palsy is 1 of the diseases critically affecting the health of children. The spasmodic type is the most common, characterized by the increased muscular tension. It often leads to lifelong disability, bringing a heavy economic burden to families and society. As a key treatment in traditional Chinese medicine, pediatric massage has a significant clinical effect on cerebral palsy in children; however, high-quality randomized controlled studies are lacking. The main objective of this study was to evaluate the efficacy of pediatric massage for children with spastic cerebral palsy. METHODS/DESIGN: The study will be a multicenter, single-blinded, randomized-controlled pilot trial. During the period from June 2019 to December 2020, 182 children with spastic cerebral palsy will be randomly divided into experimental and control groups in a 1:1 ratio. The experimental group will undergo the modified selective spinal massage method combined with the basic rehabilitation treatment, while only the basic rehabilitation treatment would be performed for the control group. The intervention period of the study will last 12 weeks, 5 days weekly on weekdays. The primary outcomes include a modified Ashworth scale assessment and gross motor function test. The secondary outcomes include the 4-diagnostic scale of Chinese medicine and children's intelligence. The observation index will be measured during the complete 12 weeks duration after the treatment of the child, that is, before treatment, after 4 weeks of treatment, after 8 weeks, and after 12 weeks of treatment. DISCUSSION: This study aims to evaluate the efficacy of pediatric massage on children with spastic cerebral palsy; if the outcome is positive, it can provide a reference for the further promotion and application of pediatric massage in the treatment of spastic cerebral palsy. TRIAL REGISTRATION: Chinese ClinicalTrials.gov, ID: ChiCTR1900021666. Acupuncture-Moxibustion Clinical Trial Registry, AMCTR: (AMCTR-IPR-19000260) Registered on 04 March 2019.

Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma.

BACKGROUND: Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). METHODS: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. RESULTS: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 µM for QGY7703and 4.04 µM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. CONCLUSIONS: The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

Significantly Improving the Crystal Growth of a Cu2ZnSn(S,Se)4 Absorber Layer by Air-Annealing a Cu2ZnSnS4 Precursor Thin Film.

The crystal quality of a Cu2ZnSn(S,Se)4 (CZTSSe) thin film is crucially important to a high-performance CZTSSe solar cell. After selenization, a bilayer CZTSSe thin film consisting of a large-grain top layer and a small-particle bottom layer is usually observed according to the literature. In this work, a facile air-annealing pretreatment is conducted for a Cu2ZnSnS4 precursor thin film prior to selenization, which can lead to sodium diffusion into the CZTS precursor thin film and surface oxidization of the CZTS thin film. Our experimental results revealed that the Na prediffusion and the surface oxidation of the CZTS precursor thin film can significantly promote the crystal growth of the CZTSSe thin film, which can completely remove the small-particle bottom layer and form a large-grain-spanned CZTSSe thin film. As a result, a photoelectric conversion efficiency of 9.80% was achieved by this method.

The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer.

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is hyperactivated in lung cancer and regulates a broad range of cellular processes, including proliferation, survival, angiogenesis, and metastasis. Thus PI3K is considered a promising target for therapy. To date, PI3K inhibitors have not been approved for lung cancer. Recent studies showed that the antipsychotic agent flupentixol induced apoptosis of lung cancer cell, however the anti-tumor mechanism of flupentixol remains unclear. Methods: (1) The idock software simulated the molecular docking between the PI3Kα protein and flupentixol. (2) Inhibition of PI3Kα by the flupentixol was examined by in vitro kinase assays. (3) The cytotoxicity of flupentixol on the NSCLC cell lines was tested by MTT assays. (4) We treated A549 and H661 cells with flupentixol and then measured the percentage of apoptotic cells by the Annexin V/PI analysis. (5) We investigated the effect of flupentixol on the expression of critical PI3K/AKT signaling pathway proteins, further analyzed on the cleavage of PARP and caspase-3 by Western blotting. (6) BALB/C nude mice were subcutaneously injected with A549 cells to evaluate the effect of flupentixol on the growth of lung carcinoma. Results: Structural analysis of the predicted binding conformation suggested that flupentixol docks to the ATP binding pocket of PI3Kα. Kinase assays demonstrate that flupentixol indeed inhibited the PI3Kα kinase activity. Flupentixol exhibited cytotoxicity in lung cancer cell lines A549 and H661 in a dose- and time-dependent manner. Furthermore, flupentixol more strongly inhibited the phosphorylation of AKT (T308 and S473) and the expression of its downstream target gene Bcl-2 than two known PI3K inhibitors (BYL719 and BKM120). Flupentixol induced apoptosis as measured by PARP and caspase-3 cleavage. Finally, flupentixol significantly suppressed A549 xenograft growth in BALB/C nude mice. Conclusions: Flupentixol could be docked to the PI3Kα protein and specifically inhibit the PI3K/AKT pathway and survival of lung cancer cells in vitro and in vivo. As an old drug, flupentixol is a new PI3K inhibitor that may be used for the treatment of lung cancers.

Manganese-Enhanced Magnetic Resonance Imaging for Detection and Characterization of Colorectal Cancers.

Here, we investigated the diagnostic performance of manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) in colorectal cancer (CRC). The ability of CRC cell lines SW620 and SW480 to uptake Mn was evaluated and compared with a normal colon cell using MEMRI. Subcutaneous xenografts in nude mice underwent MRI examination at tumor sizes of 5, 10, and 15 mm. Contrast enhancement was compared between gadolinium (Gd)- and Mn-enhanced MRI. SW620 and SW480 cell lines took up more Mn2+ than normal cells, resulting in 4.5 and 2 times greater T1 value shortening than normal cell using in vitro MEMRI (P < .001). Most xenografts (17/23) enhanced markedly on MEMRI. A heterogeneous enhancement pattern invariably noted whether Mn or Gd agents were administered, but tumors imaged using MEMRI showed a greater degree of enhancement with a larger extent of enhanced area than those imaged using Gd-enhanced MRI. The numbers of markedly Mn-enhanced cases were more in the 5-mm-size tumor group than in 10- or 15-mm-size tumor groups. Overall, MEMRI could enhance CRCs and it showed potential in detecting early small lesions and markedly enhancing tumors that had minimal Gd enhancement.

Discovery of rafoxanide as a dual CDK4/6 inhibitor for the treatment of skin cancer.

Since cyclin­dependent kinases 4/6 (CDK4/6) play pivotal roles in cell cycle regulation and are overexpressed in human skin cancers, CDK4/6 inhibitors are potentially effective drugs for skin cancer. In the present study, we present a mixed computational and experimental study attempting to repurpose approved small­molecule drugs as dual CDK4/6 inhibitors for skin cancer treatment. We performed structure­based virtual screening using the docking software idock, targeting an ensemble of CDK4/6 structures. We identified and selected nine compounds with significant predicted scores, and evaluated their cytotoxic effects in vitro in A375 and A431 human skin cancer cell lines. Rafoxanide was found to exhibit the highest cytotoxic effects (IC50: 1.09 µM for A375 and 1.31 µM for A431 cells). Consistent with the expected properties of CDK4/6 inhibitors, rafoxanide significantly increased the G1 phase population. Notably, we revealed that rafoxanide specifically decreased the expression of CDK4/6, cyclin D, retinoblastoma protein (Rb) and the phosphorylation of CDK4/6 and Rb. Furthermore, the anticancer effect of rafoxanide was demonstrated in vivo in BALB/C nude mice subcutaneously xenografted with human skin cancer A375 cells. Rafoxanide (40 mg/kg, i.p.) exhibited significant antitumor activity, comparable to that of oxaliplatin (5 mg/kg, i.p.). The combined administration of rafoxanide and oxaliplatin produced a synergistic therapeutic effect. To the best of our knowledge, the present study is the first to indicate that rafoxanide inhibits CDK4/6 activity and is a potential candidate drug for the treatment of human skin cancer.

Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells.

The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in many cellular processes, including the proliferation, survival and differentiation of lung cancer cells. Thus, PI3K is a promising therapeutic target for lung cancer treatment. In this study, we applied free and open-source protein-ligand docking software, screened 3167 FDA-approved small molecules, and identified putative PI3Kα inhibitors. Among them, econazole nitrate, an antifungal agent, exhibited the highest activity in decreasing cell viability in pathological types of NSCLC cell lines, including H661 (large cell lung cancer) and A549 (adenocarcinoma). Econazole decreased the protein levels of p-AKT and Bcl-2, but had no effect on the phosphorylation level of ERK. It inhibited cell growth and promote apoptosis in a dose-dependent manner. Furthermore, the combination of econazole and cisplatin exhibited additive and synergistic effects in the H661 and A549 lung cancer cell lines, respectively. Finally, we demonstrated that econazole significantly suppressed A549 tumor growth in nude mice. Our findings suggest that econazole is a new PI3K inhibitor and a potential drug that can be used in lung cancer treatment alone or in combination with cisplatin.

Manganese-enhanced MRI for the detection of metastatic potential in colorectal cancer.

BACKGROUND: To study manganese superoxide dismutase (MnSOD) expression, manganese-enhanced magnetic resonance imaging (MEMRI) appearance and its relation to metastatic potential in colorectal cancer (CRC). METHODS: CRC cells SW620, HCT116, LoVo, SW480, DLD-1, HCT15, Caco-2 and their normal counterpart CCD841 CoN were chosen, based on differential aggressiveness, to undergo Western blot analysis for assessment of MnSOD expression, reported as proportion of readings to internal reference (glyceraldehyde-3-phosphate-dehydrogenase). Based on the results of the invasion assay, HCT15, DLD-1, LoVo and SW620 cells and corresponding xenografts underwent MEMRI. The differences of average T1-value shortening were compared. RESULTS: MnSOD expression in SW620, HCT116, LoVo, SW480, DLD-1, HCT15, Caco-2 and CCD841 CoN cells (0.255 ± 0.018 (mean ± standard deviation), 0.289 ± 0.028, 0.438 ± 0.028, 0.337 ± 0.025, 0.777 ± 0.031, 1.045 ± 0.038, 0.163 ± 0.035 and 0.185 ± 0.038, respectively) was not correlated with Invasion Index (22.6 ± 0.7, 17.0 ± 0.6, 20.9 ± 0.6, 9.7 ± 0.4, 7.5 ± 0.3, 8.3 ± 0.2, 12.6 ± 0.5 and 0) (r = - 0.204, p = 0.627). In highly aggressive cells (SW620, LoVo), T1 shortening (289.33 ± 0.57, 268.45 ± 6.87 ms, respectively) was greater than that in lower counterparts (148.68 ± 3.99 ms in DLD-1, 128.60 ± 1.96 in HCT15) (p < 0.001). Both 5- and 10-mm group SW620 and/or LoVo tumours showed greater T1 shortening (≥600 ms) than DLD-1 and HCT15 (≤350 ms) (p < 0.001, p = 0.005, p = 0.010). CONCLUSIONS: MEMRI has the potential to noninvasively distinguish different metastatic potential CRCs. However, the MnSOD expression is not correlated to malignant potential in CRC cells.

In silico prediction and in vitro and in vivo validation of acaricide fluazuron as a potential inhibitor of FGFR3 and a candidate anticancer drug for bladder carcinoma.

Bladder carcinoma (BC) is the ninth most common cause of cancer worldwide. Surgical resection and conventional chemotherapy and radiotherapy will ultimately fail due to tumor recurrence and resistance. Thus, the development of novel treatment is urgently needed. Fibroblast growth factor receptor 3 (FGFR3) is an important and well-established target for BC treatment. In this study, we utilized the free and open-source protein-ligand docking software idock to prospectively identify potential inhibitors of FGFR3 from 3,167 worldwide approved small-molecule drugs using a repositioning strategy. Six high-scoring compounds were purchased and tested in vitro. Among them, the acaricide drug fluazuron exhibited the highest antiproliferative effect in human BC cell lines RT112 and RT4. We further demonstrated that fluazuron treatment significantly increased the percentage of apoptosis cells, and decreased the phosphorylation level of FGFR3 and its downstream proteins FRS2-α, AKT, and ERK. We also investigated the anticancer effect of fluazuron in vivo in BALB/C nude mice subcutaneously xenografted with RT112 cells. Our results showed that oral treatment with fluazuron (80 mg/kg) significantly inhibited tumor growth. These results suggested for the first time that fluazuron is a potential inhibitor of FGFR3 and a candidate anticancer drug for the treatment of BC.

Adapalene inhibits the activity of cyclin-dependent kinase 2 in colorectal carcinoma.

Cyclin-dependent kinase 2 (CDK2) has been reported to be overexpressed in human colorectal cancer; it is responsible for the G1­to­S­phase transition in the cell cycle and its deregulation is a hallmark of cancer. The present study was the first to use idock, a free and open­source protein­ligand docking software developed by our group, to identify potential CDK2 inhibitors from 4,311 US Food and Drug Administration­approved small molecular drugs with a re­purposing strategy. Among the top compounds identified by idock score, nine were selected for further study. Among them, adapalene (ADA; CD271,6­[3­(1­adamantyl)­4­methoxyphenyl]­2­naphtoic acid) exhibited the highest anti­proliferative effects in LOVO and DLD1 human colon cancer cell lines. Consistent with the expected properties of CDK2 inhibitors, the present study demonstrated that ADA significantly increased the G1­phase population and decreased the expression of CDK2, cyclin E and retinoblastoma protein (Rb), as well as the phosphorylation of CDK2 (on Thr­160) and Rb (on Ser­795). Furthermore, the anti­cancer effects of ADA were examined in vivo on xenograft tumors derived from DLD1 human colorectal cancer cells subcutaneously inoculated in BALB/C nude mice. ADA (20 mg/kg orally) exhibited marked anti­tumor activity, comparable to that of oxaliplatin (40 mg/kg), and dose­dependently inhibited tumor growth (P<0.05), while combined administration of ADA and oxaliplatin produced the highest therapeutic effect. To the best of our knowledge, the present study was the first to indicate that ADA inhibits CDK2 and is a potential candidate drug for the treatment of human colorectal cancer.

In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Surgical resection and conventional chemotherapy and radiotherapy ultimately fail due to tumor recurrence and HCC's resistance. The development of novel therapies against HCC is thus urgently required. The cyclin-dependent kinase (CDK) pathways are important and well-established targets for cancer treatment. In particular, CDK2 is a key factor regulating the cell cycle G1 to S transition and a hallmark for cancers. In this study, we utilized our free and open-source protein-ligand docking software, idock, prospectively to identify potential CDK2 inhibitors from 4,311 FDA-approved small molecule drugs using a repurposing strategy and an ensemble docking methodology. Sorted by average idock score, nine compounds were purchased and tested in vitro. Among them, the anti-psychotic drug fluspirilene exhibited the highest anti-proliferative effect in human hepatocellular carcinoma HepG2 and Huh7 cells. We demonstrated for the first time that fluspirilene treatment significantly increased the percentage of cells in G1 phase, and decreased the expressions of CDK2, cyclin E and Rb, as well as the phosphorylations of CDK2 on Thr160 and Rb on Ser795. We also examined the anti-cancer effect of fluspirilene in vivo in BALB/C nude mice subcutaneously xenografted with human hepatocellular carcinoma Huh7 cells. Our results showed that oral fluspirilene treatment significantly inhibited tumor growth. Fluspirilene (15 mg/kg) exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil (10 mg/kg). Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect. These results suggested for the first time that fluspirilene is a potential CDK2 inhibitor and a candidate anti-cancer drug for the treatment of human hepatocellular carcinoma. In view of the fact that fluspirilene has a long history of safe human use, our discovery of fluspirilene as a potential anti-HCC drug may present an immediately applicable clinical therapy.