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Osteosarcoma (OS) remains one of the most threatening primary malignant human tumors of the bone, especially in the first or second decade of life. Unfortunately, the clinical therapeutic efficacy has not substantially improved over the past four decades. Therefore, to achieve efficient tumor eradication, a new approach to prevent tumor recurrence is urgently needed. Here, we develop a new bisphosphonate (BP)-loaded microarc oxidation (MAO) coated magnesium-strontium (Mg-Sr) alloy pellet that can inhibit OS, and we illuminate the cellular and molecular mechanisms of the inhibiting effect. To generate such pellets, nitrogen-containing BP is chemically conjugated with a MAO coating on hollow Mg-Sr alloys. We demonstrate that BP coated Mg pellet has multiple desired features for OS therapy through in vitro and in vivo studies. At the cellular level, BP coated Mg pellets not only induce apoptosis and necrosis, as well as antitumor invasion of OS cells in the two-dimensional (2D) cell culture environment, but also damage the formation of multicellular tumor spheroids by OS cell lines in the three-dimensional (3D) cell culture environment. At the in vivo level, BP coated Mg pellets can destroy tumors and prevent neoplasm recurrence via synergistic Mg degradation and drug release. It is further suggested that the superior inhibitory effect on OS of our pellet is achieved by inhibiting the mevalonate pathway at the molecular level. Hence, these results collectively show that the BP coated Mg pellet is a promising candidate for future applications in repairing defects after tumor removal in OS therapy.

BACKGROUND: Previous studies have suggested that the functions of prolyl hydroxylase 3 (PHD3) in tumor growth, apoptosis and angiogenesis are essentially dependent on hypoxia-inducible factor (HIF)-1α signaling. Nevertheless, whether PHD3 represents a promising tumor suppressor target remains to be clarified. To provide insight into the therapeutic potential of PHD3 in lung cancer, this study examined the effects of PHD3 expression on HIF-1α and pyruvate kinase M2 (PKM2), as well as on lung cancer cell proliferation, migration, and invasion. METHODS: The model of hypoxia was established in A549 and SK-MES-1 cells with 200 µM CoCl2 treatment, and verified by western blot and immunocytochemical staining. The expression levels of PKM2 and HIF-1α were determined by western blot after overexpression or depletion of PHD3 in A549 and SK-MES-1 cells. In addition, cell viability, migration and invasion were measured, respectively. RESULTS: Establishment of hypoxia in A549 and SK-MES-1 cells resulted in significant decreases in PHD3 expression and remarkable increase in PKM2 expression in 24 hrs. Overexpression of PHD3 in A549 and SK-MES-1 cells decreased HIF-1α and PKM2 expression. In contrast, PHD3 knockdown increased HIF-1α and PKM2 (P

Aims Epithelial-mesenchymal transition (EMT) is one of the important regulators of metastasis in advanced hepatocellular carcinoma (HCC). Blocking the Notch signaling pathway and then reversing the EMT process is a hot spot in clinical tumor research. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 (a key cleavage enzyme of Notch pathway) inhibitor ZLDI-8 we found before on the metastasis of hepatocellular carcinoma in vitro and in vivo. Main methods The cell viability of HCC cells was evaluated by MTT and colony formation assays. Migration and invasion were assessed respectively with wound healing and transwell assays. The expression and location of proteins were detected by western blot and immunofluorescence, respectively. The effects of ZLDI-8 on metastasis of liver cancer in vivo were investigated in a tail vein injection model. Key findings In the present work, ZLDI-8 significantly inhibited proliferation, migration, invasion and EMT phenotype of highly aggressive MHCC97-H and LM3 cells. Moreover, ZLDI-8 could inhibit the migration and invasion of HepG2 and Bel7402 cells induced by TGF-β1. ZLDI-8 suppressed the protein expression of interstitial markers and increased that of epithelial markers. Meanwhile, ZLDI-8 decreased the expression of proteins in the Notch signaling pathway. Finally, ZLDI-8 blocks metastasis in the lung metastasis model in vivo. Significance ZLDI-8 suppressed the metastasis of hepatocellular carcinoma, which was associated with reversing the EMT process and regulating Notch signaling pathway. The study laid the foundation for the discovery of drugs that reverse EMT to inhibit advanced HCC metastasis.

Background Aptamers have been widely used as targeted therapeutic agents due to its relatively small physical size, flexible structure, high specificity, and selectivity. Aptamers functionalized nanomaterials, not only enhance the targeting of nanomaterials, but can also improve the stability of the aptamers. We developed aptamer C2NP (Apt) conjugated straight DNA nanotubes (S-DNT-Apt) and twisted DNA nanotubes (T-DNT-Apt) as nanocarriers for doxorubicin (DOX). Methods The twisted DNA nanotubes (T-DNT) and straight DNA nanotubes (S-DNT) were assembled with a scaffold and hundreds of staples. Apt was site-specifically anchored on DNA nanotubes with either different spatial distribution (3 or 6 nm) or varied stoichiometry (15Apt or 30Apt). The developed nanocarriers were characterized with agarose gel electrophoresis and transmission electron microscopy. The drug loading and release in vitro were evaluated by measuring the fluorescence intensity of DOX using a microplate reader. The stability of DNT in cell culture medium plus 10% of FBS was evaluated by agarose gel electrophoresis. The cytotoxicity of DNA nanostructures against K299 cells was tested with a standard CCK8 method. Cellular uptake, cell apoptosis, cell cycle and reactive oxygen species level were investigated by flow cytometry. The expression of p53 was examined by Western Blot. Results T-DNT-30Apt-6 exhibited the highest cytotoxicity when the concentration of Apt was 120 nM. After intercalation of DOX, the cytotoxicity of DOX@T-DNT-30Apt-6 was further enhanced due to the combination of chemotherapy of DOX and biotherapy of Apt. The enhanced cytotoxicity of DOX@T-DNT-30Apt-6 can be explained by the increase in the cellular uptake, cell apoptosis and intracellular ROS levels. Additionally, the interaction between Apt and its receptor CD30 could upregulate the expression of p53. Conclusion These results demonstrate that both stoichiometry and spatial arrangement of Apt on T-DNT-Apt influence the anticancer activity. The developed twisted DNA nanotubes may be a solution for the synergistic treatment of cancer.

Smart delivery of therapeutic peptides that target cellular signaling pathways holds high specificity and great promise for cancer therapy. Here, DNA tetrahedrons (TDs) are designed to carry two therapeutic peptides-FAS peptide and FK-16 peptide. DNA TDs are designed with varied numbers and spatial placement of FAS peptides and FK-16 peptides, and tested for their anti-cancer efficacy. Trimerization of FAS receptors using TDs that are assembled with three FAS peptides enhances FAS-induced cell apoptosis. FK-16 peptides are conjugated to TDs via a peptide sequence sensitive to MMP-2/9 in tumor microenvironment. Therefore, FK-16 peptides are expected to detach from TDs once arrived the tumor microenvironment. A cell penetrating peptide (TAT) is also conjugated to the FK-16 peptide to facilitate its intracellular delivery, which increases the FK-16 peptide-induced cell apoptosis and autophagy. TD-3(TFM)3(FAS) (TFM: TAT + FK-16 + MMP-2/9) exhibits the highest HT-29 inhibition in vitro and in vivo among all therapies. In addition to the high anti-cancer efficacy, TD-3(TFM)3(FAS) shows a high specificity to HT-29 cells in vitro and in vivo. Low cell inhibition rates and cellular uptake are observed in normal cells. In sum, the multifunctional TD-3(TFM)3(FAS) provides a new platform for the smart delivery of anti-cancer peptides to achieve enhanced efficacy and high specificity.

Radical therapy takes advantage of the reactive oxygen species produced in greater quantities within tumor cells than in normal cells. Here, for the first time, we explore a TiO

The mechanisms underlying the immune defense by trophoblasts against pathogens remain ill defined. We demonstrated that placental cell death was increased upon in vivo exposure to Listeria monocytogenes. The death of infected cells is an important host innate defense mechanism. Meanwhile, double-stranded DNA (dsDNA) derived from intracellular bacteria or dsDNA viruses is emerging as a potent pathogen-associated molecular pattern recognized by host cells. We sought to characterize trophoblast death in response to cytosolic dsDNA challenge. Our results showed that dsDNA induced caspase-dependent and -independent cell death in human trophoblasts. However, necroptosis, a cell death pathway independent of caspase, could not be induced by dsDNA treatment, even in the presence of exogenously expressed RIPK3. L. monocytogenes-derived genomic DNA triggered a similar cell death pattern. Moreover, the cell death in response to dsDNA was IFI16 dependent. These data suggest that cytosolic dsDNA induces nonnecroptotic cell death in trophoblasts via IFI16, and this could contribute to placental barrier against infection.

Polypeptide from Chlamys farreri (PCF, molecular mass is 879) is a new marine polypeptide compound isolated from Chlamys farreri. This study investigates the possible protective roles and the mechanism of PCF against ultraviolet B (UVB)-induced apoptosis in murine thymocytes.The rate of apoptosis and caspase-3 activation was measured by flow cytometry. The expression of stress-response genes c-fos and c-jun was observed by RT-PCR. Western blot analysis was performed to determine the release of cytochrome c.It was found that UVB induced murine thymocyte death. The cells treated with UVB showed an increase in cytochrome c release, caspase-3 activity, as well as in the expression of c-fos and c-jun. In addition, all were involved in UVB-induced cell apoptosis.Our present observations pointed to the ability of PCF to avert UVB-induced apoptosis in thymocytes by modulating c-fos and c-jun expression, cytochrome c release, and the consequent activation of caspase-3, which were essential components of the UV-induced cell apoptotic pathway. The results suggested that PCF is a promising protective substance against UV radiation.

Expression of survivin, an apoptosis suppressor gene, in colorectal cancer(CRC), and its relationship with pathologic factors, cell apoptosis, and angiogenesis are unclear. This study aimed to investigate the effect of survivin on cell apoptosis, and its relation with angiogenesis, and to further explore the effects of survivin on development and prognosis of CRC.Protein expression of survivin, and vascular endothelial growth factor (VEGF) in 91 specimens of CRC was detected by immunohistochemistry, apoptosis index (AI) of tumor cells was detected by TUNEL method.Positive rate of survivin in CRC with distant metastasis was 56.0% (14/25), significantly higher than that in CRC without metastasis (48.5%, 32/66) (P0.05); and that in 5-year survival patients(42.9%,30/70) was lower than that in patients died within 5 years (76.2%,16/21) (P0.01). The average survival time of patients with positive expression of survivin was 91.3 months, and that of patients with negative expression of survivin was 116.4 months; 5-year survival rate of the former (65.2%, 30/46) was significantly lower than that of the latter (88.9%, 40/45) (P0.01). The average AI of patients with positive expression of survivin was lower than that of patients with negative expression of survivin [(0.74+/-0.19)% vs. (1.07+/-0.24)%, P0.01]; the expression of survivin significantly correlated with that of VEGF (pearson: 0.721).Survivin may promote metastasis, and affect prognosis of CRC through inhibiting cell apoptosis, and regulating angiogenesis of CRC.

Survivin, a novel inhibitor of apoptosis, expressing in a cell cycle-dependent manner,regulates the G(2)/M phase of the cell cycle by associating with mitotic spindle microtubules; it directly inhibits caspase-3 and caspase-7activity. During tumorigenesis, survivin expression is inversely correlated with apoptosis and is positively correlated with proliferation and angiogenesis. Survivin expression up-regulation predicts short survival and poor prognosis in human cancers. Survivin targeting antisense nucleotide and survivin mutants induce apoptosis, reduce tumor growth potential, and sensitize tumor cells to chemotherapeutic drugs and X-irradiation in vitro and in vivo. These results suggest that survivin may has the potential function as a new target for the diagnosis and treatment of cancer.