Co-inhibition of Aurora A and Haspin kinases enhances survivin blockage and p53 induction for mitotic catastrophe and apoptosis in human colorectal cancer.

Colorectal cancer (CRC) is a leading cause and mortality worldwide. Aurora A and haspin kinases act pivotal roles in mitotic progression. However, the blockage of Aurora A and Haspin for CRC therapy is still unclear. Here we show that the Haspin and p-H3T3 protein levels were highly expressed in CRC tumor tissues of clinical patients. Overexpression of Haspin increased the protein levels of p-H3T3 and survivin in human CRC cells; conversely, the protein levels of p-H3T3 and survivin were decreased by the Haspin gene knockdown. Moreover, the gene knockdown of Aurora A induced abnormal chromosome segregation, mitotic catastrophe, and cell growth inhibition. Combined targeted by co-treatment of CHR6494, a Haspin inhibitor, and MLN8237, an Aurora A inhibitor, enhanced apoptosis and CRC tumor inhibition. MLN8237 and CHR6494 induced abnormal chromosome segregation and mitotic catastrophe. Meanwhile, MLN8237 and CHR6494 inhibited survivin protein levels but conversely induced p53 protein expression. Ectopic survivin expression by transfection with a survivin-expressed vector resisted the cell death in the MLN8237- and CHR6494-treated cells. In contrast, the existence of functional p53 increased the apoptotic levels by treatment with MLN8237 and CHR6494. Co-treatment of CHR6494 and MLN8237 enhanced the blockage of human CRC xenograft tumors in nude mice. Taken together, co-inhibition of Aurora A and Haspin enhances survivin inhibition, p53 pathway induction, mitotic catastrophe, apoptosis and tumor inhibition that may provide a potential strategy for CRC therapy.

Expression of survivin and p53 modulates honokiol-induced apoptosis in colorectal cancer cells.

Honokiol is a small biphenolic compound, which exerts antitumor activities; however, the precise mechanism of honokiol-induced apoptosis in the human colorectal cancer cells remains unclear. Here, we show that survivin and p53 display the opposite role on the regulation of honokiol-induced apoptosis in the human colorectal cancer cells. Honokiol induced the cell death and apoptosis in various colorectal cancer cell lines. Moreover, honokiol elicited the extrinsic death receptor pathway of DR5 and caspase 8 and the intrinsic pathway of caspase 9. The common intrinsic and extrinsic downstream targets of activated caspase 3 and PARP protein cleavage were induced by honokiol. Interestingly, honokiol reduced anti-apoptotic survivin protein and gene expression. Transfection with a green fluorescent protein (GFP)-survivin-expressed vector increased the colorectal cancer cell viability and resisted the honokiol-induced apoptosis. Meantime, honokiol increased total p53 and the phosphorylated p53 proteins at Ser15 and Ser46. The p53-wild type colorectal cancer cells were exhibited greater cytotoxicity, apoptosis and survivin reduction than the p53-null cancer cells after treatment with honokiol. Together, these findings demonstrate that the existence of survivin and p53 can modulate the honokiol-induced apoptosis in the human colorectal cancer cells.

The depletion of securin enhances butein-induced apoptosis and tumor inhibition in human colorectal cancer.

Butein (3,4,2',4'-tetrahydroxychalcone) is a promising natural polyphenolic compound that shows the growth inhibitory activity in human cancer cells; however, the precise mechanism is still unclear. Securin plays pivotal role in cancer cell proliferation and tumorigenesis. Here, we report the presence of securin that could modulate apoptosis and tumor growth ability in the butein-treated human colorectal cancer. Butein induced caspase-3 activation and PARP protein cleavage for apoptosis induction in human colorectal cancer cells. Interestingly, butein reduced the securin protein levels but conversely increased the phospho-histone H3 proteins, mitotic arrest and abnormal chromosomes segregation in cancer cells. The securin-null colorectal cancer cells were more sensitive on the reduction of cell viability than the securin-wild type cancer cells following butein treatment. The loss of securin in human colorectal cancer cells decreased tumor growth ability in nude mice. Moreover, butein reduced the tumor size of xenografted human colorectal tumors of nude mice. Taken together, this study demonstrates for the first time that the depletion of securin mediates the butein-induced apoptosis and colorectal tumor inhibition.

Loss measurement of plasmonic modes in planar metal-insulator-metal waveguides by an attenuated total reflection method.

We report experimental excitation and characterization of surface plasmon modes in planar metal-insulator-metal (MIM) waveguides. Our approach is based on determining the width of the reflection angular spectrum in the attenuated total reflection (ATR) configuration. Owing to its transverse character, the ATR configuration provides a more straightforward and simpler way to determine the loss of plasmonic modes in MIM structures, compared to using tapered end couplers with multiple waveguide samples or scanning near-field optical microscopy. In this Letter, two waveguide structures with Au claddings and 50/200 nm SiO(2) cores are investigated. The propagation lengths measured at λ = 1.55 µm are 5.7 and 18 µm, respectively, in agreement with the theoretical predictions.

Characterization of the loss of plasmonic modes in planar metal-insulator-metal waveguides by a coupling-simulation approach.

Metal-insulator-metal (MIM) structures have been the subject of great interest as nanoscale plasmonic waveguides. The modeling and measurement of the loss in these waveguides is one of the critical issues in realizing the plasmon-based nanocircuitry. Due to the subwavelength size of the structure, the light injection and the measurement of the loss in MIM structures typically require tapered fibers or waveguides, as well as multiple waveguide structures with various length scales 8 9 or scanning near-field optical microscopy. The transverse transmission/reflection (TTR) method is presented for determining the loss of plasmonic modes in MIM waveguides. The approach is based on determining the width of the reflection angular spectrum in the attenuated total reflection configuration. Owing to its transverse character, the TTR method potentially provides a more straightforward and simpler way to determine the loss of plasmonic modes in MIM structures.

Attenuation and mode profile determination of leaky/lossy modes in multilayer planar waveguides by a coupling simulation method.

Leaky planar waveguides are critically important to the operation of present day and future integrated photonic circuits. However, to incorporate these waveguides successfully into practical photonic circuits requires an accurate knowledge of their attenuation and mode profile in operation. In contrast with previous numerical methods for obtaining leaky waveguide characteristics, which usually involve complicated algorithms to solve for the complex roots of boundary conditions, the transverse transmission/reflection (TTR) method presented here provides a straightforward and simple approach by simulating the corresponding coupled-waveguide structure. By adding a high-index layer adjacent to the cover to enable the coupling, the transmission/reflection coefficients are shown to be definitively expressed in the form of a Lorentzian that is directly related to the complex propagation constant of leaky/lossy mode. The TTR method simultaneously determines the mode profile of the leaky/lossy mode via the angle of incidence for resonant transmission/reflection. In the present work, the TTR method is applied to an antiresonant reflection optical waveguide (ARROW), a lossy waveguide structure, and a waveguide structure that is simultaneously leaky and lossy.