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Introduction For some cancers bone is the preferred site for metastasis and involves a cascade involving transition of epithelial cells to mesenchymal cells and subsequent intravasation to the blood and lymph vessels, and finally hematogenous dissemination to perivascular niches of the bone marrow sinusoids. It has been shown that protein kinase C can aid metastasis to bone. Hence, pharmacological inhibition of protein kinase C (PKC) activity is thought of as a potential therapeutic option in bone metastatic lesions. The objective of the current study was to investigate how PKCs exert their effect on bone cancer metastasis and to test the efficacy of pharmacological inhibition of PKC on bone metastasis. Material and methods The effect of the PKC inhibitor Go6983 on epithelial and mesenchymal cell marker expression in the osteosarcoma cell line DAN was determined by immunoblot and immunofluorescence analysis. The in vivo effect of Go6983 was evaluated with a xenograft model using DAN cells. Results Treatment with transforming growth factor β (TGF-β) led to loss of the epithelial cell marker and gain of mesenchymal cell markers in the osteosarcoma cell line, DAN. This transition occurred concomitantly with PKC activation. TGF-β-mediated PKC activation resulted in activation of ribosomal protein 6 (S6), but not S6K1. Pharmacological inhibition of PKC activation attenuated these effects. In a xenograft model of experimental metastasis, pharmacological inhibition of PKC activation over a period of 4 weeks reduced both tumor burden and metastasis to lungs. Conclusions Our results indicate that PKC potentiates tumor metastasis to the bone by potentiating translation increase and can be putatively inhibited by pharmacological inhibition.

Tumor angiogenesis has been identified as an important factor in the development and progression of tumors, and anti-angiogenesis therapy has been recognized as an effective tumor therapy pattern. The unique characteristics of nanodiamonds (NDs) have been explored for photothermal therapy (PTT) against cancer, while the efficiency of mild PTT mediated by bare NDs was limited. The combination of different therapies into a single nanoplatform has shown great potential for synergistic cancer treatment. In this investigation, we integrated hydrophobic antiangiogenesis agent combretastatin A4 (CA4) into the protamine sulfate (PS) functionalized NDs hybrids (NDs@PS) with a noncovalent self-assembling method (CA4-NDs@PS) for potential combined anti-angiogenesis and mild photothermal therapy in liver cancer. The resulted CA4-NDs@PS NDs exhibited high drug loading ability, good dispersibility and colloidal stability. The near-infrared (NIR) laser irradiation could trigger the release of CA4 from CA4-NDs@PS NDs and elevate the temperature of CA4-NDs@PS NDs aqueous sulution. In vitro results illustrated that CA4-NDs@PS coupled with laser irradiation could remarkably enhance HepG-2 cells killing efficiency, leading to an enhanced photocytotoxicity. Furthermore, in vivo experiments revealed that CA4-NDs@PS exhibited a highly synergistic anticancer efficacy with NIR laser irradiation in HepG-2 tumor-bearing mice. Altogether, our present study fabricated a novel NDs@PS-based nanoplatform for combined anti-tumor angiogenesis and mild PTT against liver cancer.

Recent studies have identified that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important feature of osteosarcoma, where it promotes cell proliferation, survival, and chemo-resistance. Here, we studied the therapeutic potential of NVP-BEZ235, a novel dual PI3K/mTOR dual inhibitor, on osteosarcoma cells in vivo and in vitro. NVP-BEZ235 was cytotoxic and cytostatic to a panel of osteosarcoma lines (MG-63, U2OS and SaOs-2), where it induce apoptosis and cell-cycle arrest. At the molecular level, NVP-BEZ235 inhibited PI3K-AKT-mTORC1 activation and downregulated cyclin D1/cyclin B1 expressions, while increasing MEK/Erk phosphorylation in osteosarcoma cells. MEK/Erk inhibitors PD98059 and MEK-162 increased NVP-BEZ235 activity on osteosarcoma cells. In vivo, oral NVP-BEZ235 inhibited U2OS xenograft in SCID mice, and its anti-tumor efficiency was further enhanced by MEK-162 co-administration. Taken together, our findings indicate that dual inhibition of PI3K and mTOR with NVP-BEZ235, either alone or in combination with MEK/Erk inhibitors, may be an efficient treatment for osteosarcoma.

The search for novel and more efficient chemo-agents against malignant osteoblastoma is important. In this study, we examined the potential anti-osteoblastoma function of bufotalin, and studied the underlying mechanisms. Our results showed that bufotalin induced osteoblastoma cell death and apoptosis in dose- and time-dependent manners. Further, bufotalin induced endoplasmic reticulum (ER) stress activation in osteoblastoma cells, the latter was detected by the induction of C/EBP homologous protein (CHOP), phosphorylation of inositol-requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), as well as caspase-12 activation. Conversely, the ER stress inhibitor salubrinal, the caspase-12 inhibitor z-ATAD-fmk as well as CHOP depletion by shRNA significantly inhibited bufotalin-induced osteoblastoma cell death and apoptosis. Finally, by using a mice xenograft model, we demonstrated that bufotalin inhibited U2OS osteoblastoma cell growth in vivo. In summary, our results suggest that ER stress contributes to bufotalin-induced apoptosis in osteoblastoma cells. Bufotalin might be investigated as a novel anti-osteoblastoma agent.

To investigate the feasibility of posterior fixation with 3.5-mm pedicle screws in the atlantoaxial vertebrae of children.In this study, atlantoaxial vertebrae specimens were obtained from 10 cadavers of children aged 6-8 years. We measured the height and width of the C(1) pedicle and the midportion of C(1) lateral mass; the width of C(1) posterior arch under the vertebral artery groove and the height of the external and internal one-third of this part; the external, internal height and the superior, middle, inferior width of the C(2) pedicle (transverse foramen). Furthermore, computed tomography (CT) axial scan was performed on 20 age-matched volunteers to obtain relative data of their atlantoaxial vertebrae. We measured the length and width of the C(1) and C(2) pedicles in the atlantoaxial cross-sectional plane. On CT workstation, we also measured the angles between the longitudinal axes of the atlantoaxial pedicles and the midsagittal plane.For the cadaveric specimen group, the height and width of the C1 pedicle were (5.26+/-0.44) mm and (6.26+/-0.75) mm respectively. The height of the medial one-third of the C1 posterior arch under the vertebral artery groove was (4.07+/-0.24) mm. The external, internal height and superior, middle, inferior width of the C2 pedicle was (6.86+/-0.48) mm, (6.67+/-0.49) mm, (6.63+/-0.61) mm, (5.41+/-0.39) mm and (3.71+/-0.30) mm, respectively. For the volunteer group measured by CT scan, the height and width of the C(1) pedicle were (5.47+/-0.34) mm and (6.63+/-0.54) mm respectively, while (6.59+/-0.51) mm and (5.13+/-0.42) mm of the C2 pedicle. The angles between the atlas, axis pedicles and the midsagittal plane were (9.60+/-1.32) degree and (27.80+/-2.22) degree respectively.It is feasible to place a 3.5-mm pedicle screw in the C(1) and C(2) pedicles of children aged 6-8 years old.