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Most cancer therapies are suffering from side effects to varying degrees, which might compromise the body functions and long-term health of patients. Balancing treatment efficacy and side effects has become a priority. Inspired by the concept that cellular ion homeostasis can lead to apoptosis, we developed a novel therapeutic strategy by incorporating the K+ transporter valinomycin into liposomes (Lipo-VM). Valinomycin is a naturally occurring polypeptide showing good biodegradation in vivo with reduced long-term side effects. Lipo-VM facilitates the K+ efflux of cells and triggers a caspase-dependent pathway of apoptosis by causing the collapse of mitochondrial membrane potential. With the help of a liposome-based nano-delivery system, Lipo-VM shows enhanced cell uptake and accumulation at the tumor site, which results in significant inhibition of tumor growth in a liver cancer model. The proposed valinomycin-anchored liposome provides an efficient and safe approach for cancer therapy. [Display omitted] • A cancer therapeutic system of valinomycin-anchored liposomes (Lipo-VM) is proposed. • Lipo-VM shows enhanced cell uptake and accumulation at the tumor site. • Cell membrane fused Lipo-VM facilitates K+ efflux of cells inhibiting tumor growth. • A caspase-dependent pathway of apoptosis is proposed. • Lipo-VM provides an efficient and safe approach for cancer therapy. [ABSTRACT FROM AUTHOR]

In Mycobacterium tuberculosis-infected macrophages, cyclooxygenase-2 (COX-2) expression considerably increases to defend the body against mycobacteria by regulating adaptive immunity and restoring the mitochondrial inner membrane. Moreover, in cancer cells, COX-2 enhances the autophagy machinery, an important bactericidal mechanism. However, the association between M. tuberculosis-induced COX-2 and autophagy-mediated antimycobacterial response has not been explored. Here, COX-2 expression silencing reduced the autophagy and bactericidal activity against intracellular M. tuberculosis, while COX-2 overexpression reversed the above effects. In addition, enhancement of bactericidal activity was suppressed by inhibiting autophagy in COX-2-overexpressing cells, indicating that COX-2 accelerated mycobacterial elimination by promoting autophagy. Furthermore, the regulatory effects of COX-2 on autophagy were mediated by its catalytic products, which functioned through inhibiting the protein kinase B/mammalian target of rapamycin pathway. Thus, COX-2 contributes to host defense against mycobacterial infection by promoting autophagy, establishing the basis for development of novel therapeutic agents against tuberculosis by targeting COX-2. [ABSTRACT FROM AUTHOR]

Background/Aims: This study aims to identify whether Urothelial Cancer Associated 1 (UCA1) regulates mitochondrial metabolic reprogramming in bladder cancer, and to explore how UCA1 participates in mitochondrial metabolism by the UCA1/miR-195/ARL2 signaling pathway; these findings may be aid in the development of tumor diagnostic and therapeutic strategies. Methods: Bladder tissues were obtained from patients. Stable cell lines were constructed, with ectopic expression of UCA1 in UMUC2 cells and knockdown of UCA1 in 5637 cells. The expression levels of UCA1, miR-195, and ARL2 were detected by real-time PCR, western blotting, and immunohistochemistry. Cell viability was detected by Cell Counting Kit-8 (CCK8) assay; mitochondrial DNA copy numbers were tested by realtime PCR; ATP level was evaluated by ATP assay kit; mitochondrial membrane potential was analyzed by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) fluorescent probe. miRNAs between UCA1 and ARL2 were predicted by TargetScan and RNAHybrid, and then determined by real-time PCR. Dual-luciferase activity assay and RNA immunoprecipitation (RIP) assay were used to verify the relationship between UCA1 and miR-195. The expression level of ARL2 was silenced by small interfering RNA(siRNA). For in vivo experiments, UCA1-silencing 5637 cells were subcutaneously injected into BALB/C nude mice to evaluate the effects of UCA1 on tumor progression by the regulation of miR-195 and ARL2. Results: We demonstrate here that UCA1 enhances mitochondrial function in bladder cancer cells. UCA1 contributes to ARL2-induced mitochondrial activity, which plays an important role in mitochondrial function. UCA1, as a competing endogenous RNA (ceRNA), regulates mitochondrial function through upregulating ARL2. In this way, it inhibited the miR-195 signaling pathway to enhance mitochondrial function in bladder cancer. Additionally, ARL2 is a direct target of miR-195 and can be repressed by either miR-195 overexpression or UCA1 inhibition. Knockdown of ARL2 was analogous to the inhibition of UCA1 and the upregulation of miR-195. Animal experiments further indicated that UCA1 promoted bladder tumor growth by regulating miR-195/ARL2. Conclusion: These data suggest that UCA1 enhanced mitochondrial function and cell viability through the UCA1/miR-195/ARL2 axis in vitro and in vivo. The elucidation of this signaling network provides a more adequate theoretical basis for understanding the molecular pathology of bladder cancer, and also UCA1 as a potential diagnosis and treatment target for bladder cancer. [ABSTRACT FROM AUTHOR]

A strategy is proposed to achieve an enhanced capture efficiency of and low damage to human leukemic lymphoblasts (CCRF-CEM) by the synergistic effect of topographical interactions and phenylboronic acid functional groups on nanostructures. To realize this purpose, a simple and template free method to synthesize boronic acid derivative polyaniline bioinspired nanostructures with controlled morphology is established. Different nanostructured morphologies such as nanotexture, nanofibers, nanoparticles, microsphere, and 3D porous network have been prepared by controlling the nucleation and growth rate for polymerization. The phenylboronic acid functional groups on the surface of the nanostructures during poly­merization are used as artificial lectins to reversibly capture and release circulating tumor cells (CTCs) with little damage to the cells. The method presented here is simple, rapid, and highly efficient for CTC capture and release with low cost in materials and instruments. [ABSTRACT FROM AUTHOR]

Purpose: Cervical carcinoma is the second most prevalent and the fifth most deadly malignancy seen in women worldwide. Dysregulated activation of EGF ErbB system has been implicated in diverse types of human cancer; however, it is elusive how it is regulated in human cervical cancer cells. We herein aimed to explore the mechanisms of cervical carcinoma response to epidermal growth factor (EGF), with a view of the pathways activated by EGF. Methods: Using the GSE6783 affymetrix microarray data accessible from gene expression omnibus database, we first identified the differentially expressed genes between EGF-stimulated and -unstimulated samples. Then we constructed a regulation network and identified the network motifs. We also performed biological process and pathway enrichment analyses to functionally classify the genes in the regulation network. Results: A total of 11 network motifs were identified in the regulation network. EGF treatment could increase the risk of cancer via dysregulation of cancer-related pathways and immune response pathways. Conclusions: Network motif analysis is useful in mining the useful information underlying the network. We hope our work could serve as a basis for further experimentation. [ABSTRACT FROM AUTHOR]

Aim:The efficacy of the Akt inhibitor perifosine against chronic myeloid leukemia (CML) cells and its mechanisms of action are unknown. In this study, the cytotoxic effects of perifosine on CML and acute myeloid leukemia (AML) cell lines were compared to elucidate the mechanisms underlying the differences.Methods:Human AML cell lines Kasumi-1 and HL-60, and the CML cell line K562 were used. Cell viability was quantitated using MTT assay. Apoptosis was determined using Annexin V-FITC/propidium iodide and Hoechst staining, which were followed by flow cytometry and fluorescence microscopy analysis, respectively. Caspase pathway activation and the expression of autophagy-related genes were examined using Western blot. Autophagy was studied using electron microscopy, the acridine orange staining method, and GFP-LC3 was examined with fluorescence microscopy.Results:In contrast to AML cell lines, the CML cell lines K562 and K562/G (an imatinib-insensitive CML cell line) were resistant to perifosine (2.5-20 μmol/L) in respect to inhibiting cell growth and inducing apoptosis. Perifosine (2.5, 5, and 10 μmol/L) inhibited Akt and its phosphorylation in AML cells, but not in CML cells. Treatment with perifosine (20 μmol/L) resulted in autophagy in CML cells as shown by the increased formation of acidic vesicular organelles and the accumulation of LC3-II. Treatment of CML cells with perifosine (5, 10, and 20 μmol/L) dose-dependently upregulated AGT5, but not Beclin 1 at the protein level. Furthermore, inhibition of autophagy by chloroquine (40 nmol/L) significantly suppressed the cell growth and induced apoptosis in CML cells treated with perifosine (20 μmol/L).Conclusion:Our results show that CML cell lines were resistant to the Akt inhibitor perifosine in vitro, which is due to perifosine-induced protective autophagy and upregulation of ATG5. [ABSTRACT FROM AUTHOR]

Cytotoxic lymphocytes are key players in the orchestration of immune response and elimination of defective cells. We have previously reported that natural killer (NK) cells enter target tumor cells, leading to either target cell death or self-destruction within tumor cells. However, it has remained elusive as to the fate of NK cells after internalization and whether the heterotypic cell-in-cell process is different from that of the homotypic cell-in-cell event recently named entosis. Here, we show that NK cells undergo a cell-in-cell process with the ultimate fate of apoptosis within tumor cells and reveal that the internalization process requires the actin cytoskeletal regulator, ezrin. To visualize how NK cells enter into tumor cells, we carried out real-time dual color imaging analyses of NK cell internalization into tumor cells. Surprisingly, most NK cells commit to programmed cell death after their entry into tumor cells, which is distinctively different from entosis observed in the homotypic cell-in-cell process. The apoptotic cell death of the internalized NK cells was evident by activation of caspase 3 and DNA fragmentation. Furthermore, NK cell death after internalization is attenuated by the caspase inhibitor, Z-VAD-FMK, confirming apoptosis as the mode of NK cell death within tumor cells. To determine protein factors essential for the entry of NK cells into tumor cells, we carried out siRNA-based knockdown analysis and discovered a critical role of ezrin in NK cell internalization. Importantly, PKA-mediated phosphorylation of ezrin promotes the NK cell internalization process. Our findings suggest a novel regulatory mechanism by which ezrin governs NK cell internalization into tumor cells. [ABSTRACT FROM AUTHOR]

Homoharringtonine (HHT) is a plant alkaloid with antileukemic activity which is currently being used for treatment of acute and chronic leukemias. The present studies have evaluated the effect of HHT on proliferation and apoptosis in human myeloma cells. Myeloma cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic cells and cell cycle were evaluated by flow cytometry. Level of caspase-8, caspase-9, caspase-3, and DNA repair enzyme poly (ADP-ribose) polymerase (PARP), were investigated using Western blot analysis. We found that HHT significantly inhibited the proliferation of human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM in a dose-dependent manner. HHT also induced apoptosis in myeloma cells as evidenced by flow cytometric detection of annexin V binding assay. This apoptotic process was associated with the activation of caspase-8, caspase-9, caspase-3 and PARP. The results also demonstrate that HHT potentiates dexamethasone-induced killing of MM cells. These findings indicate that HHT may be effective in the treatment of MM. [ABSTRACT FROM AUTHOR]

Six new cycloartane triterpenoid saponins, thalisides A-F ( 1 – 6 ), along with four known ones ( 7 – 10 ), were isolated from Thalictrum fortunei. The new structures were elucidated by using spectroscopic data (NMR, IR, UV, and MS). Compounds 1–10 were examined for their in vitro cytotoxicity against two human cancer cell lines (HepG2, A549) and antiviral activity against influenza A virus (H1N1) and found to be inactive. [ABSTRACT FROM AUTHOR]