A Simple Method to Evaluate Structural Stability of Group IV and III-V Semiconductors

The structural stabilities of bulk Si, Ge, and GaAs are discussed based on the total energy evaluated by the summation of the band structure energy and the short-range repulsive potential between ions. The band structure energy is calculated by means of the simple tight-binding method. The tight-binding parameters are determined so as to fit to the results of a pseude potential calculation and Harrison's model is employed to include the influence of lattice deformation. The short-range-force is assumed to be of the exponential form and parameters are determined so as to reproduce an experimental value of bulk modulus. This treatment qualitatively well describes structural properties in spite of the simple computational procedure and roughly gives the known variation of the total energy for a uniaxial strain. This method is able to be applied to an investigation of the structural stabilities of superlattices, for example, a strained layer superlattice consisting of hetero-semiconductors

Bortezomib Reduces the Tumorigenicity of Multiple Myeloma via Downregulation of Upregulated Targets in Clonogenic Side Population Cells

Side population (SP) cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11) express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2 gamma nul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3) express genes involved in the cell cycle and mitosis (e. g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM), polycomb (e. g., EZH2, EPC1) and ubiquitin-proteasome (e. g., UBE2D3, UBE3C, PSMA5) more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680) and a proteasome inhibitor (bortezomib) with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3) and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma

Hypoxia‐induced oxidative stress promotes therapy resistance via upregulation of heme oxygenase‐1 in multiple myeloma

Abstract Background Multiple myeloma (MM) is a hematopoietic malignancy for which proteasome inhibitors have become available in recent years. However, many patients develop resistance to these drugs during treatment. Therefore, it is important to elucidate the mechanisms underlying resistance acquisition by proteasome inhibitors. Side population (SP) cells, which have a high drug efflux capacity and hypoxic responses in the microenvironment have both provided important insights into drug resistance in MM; however, little is known about the characteristics of SP cells in hypoxic microenvironments. Methods We performed cDNA microarray analysis for SP and non‐SP obtained from RPMI‐8226 and KMS‐11 cell lines cultured for 48 h in normoxic and hypoxic conditions (1% O2). Genes specifically upregulated in hypoxic SP were examined. Results Our comprehensive gene expression analysis identified HMOX1, BACH2, and DUX4 as protein‐coding genes that are specifically highly expressed in SP cells under hypoxic conditions. We have shown that HMOX1/heme oxygenase‐1 (HMOX1/HO‐1) is induced by hypoxia‐inducible reactive oxygen species (ROS) and reduces ROS levels. Furthermore, we found that HMOX1 contributes to hypoxia‐induced resistance to proteasome inhibitors in vitro and in vivo. Excessive ROS levels synergistically enhance bortezomib sensitivity. In clinical datasets, HMOX1 had a strong and significantly positive correlation with MAFB but not MAF. Interestingly, hypoxic stimulation increased MAFB/MafB expression in myeloma cells; in addition, the knockdown of MAFB under hypoxic conditions suppressed HMOX1 expression. Conclusion These results suggest that the hypoxia‐ROS‐HMOX1 axis and hypoxia‐induced MafB may be important mechanisms of proteasome inhibitor resistance in hypoxic microenvironments

Bortezomib Reduces the Tumorigenicity of Multiple Myeloma via Downregulation of Upregulated Targets in Clonogenic Side Population Cells

<div><p>Side population (SP) cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11) express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3) express genes involved in the cell cycle and mitosis (e.g., <i>CCNB1, CDC25C, CDC2</i>, <i>BIRC5, CENPE, SKA1</i>, <i>AURKB, KIFs</i>, <i>TOP2A, ASPM</i>), polycomb (e.g., <i>EZH2, EPC1</i>) and ubiquitin-proteasome (e.g., <i>UBE2D3, UBE3C, PSMA5</i>) more strongly than do non-SP cells. Moreover, <i>CCNB1, AURKB</i>, <i>EZH2</i> and <i>PSMA5</i> were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680) and a proteasome inhibitor (bortezomib) with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3) and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.</p> </div

Cell cycle analysis of SP and MP of MM cell lines.

<p>(A). Cell cycle pattern of RPMI 8226 cell with and without Hoechst 33342 stain. (B). Cell cycle analysis of RPMI 8226 SP cells and CD138⁺ and CD138⁻ MP cells. % of each cell cycle phase is as follows; SP: G₀/G₁ 34.5%, S 35.1%, G₂/M 30.4%, CD138⁺MP: G₀/G₁ 44.0%, S 50.5%, G₂/M 0.90%, CD138⁻MP: G₀/G₁ 84.1%, S 15.3%, G₂/M 0.61%. (C). G₀/G₁, S, and G₂/M fractions (%) among SP, CD138⁺ MP and CD138⁻ MP cells in RPMI 8226. Bars are means ± SD of three independent experiments. (D–F). Cell cycle analysis of SP and MP cells from the AMO1 (D), KMS-12-BM (E) and KMS-11 (F) cell lines. Cell cycle patterns in SP and MP cells from the indicated lines are shown beside bar graphs of %SP and %MP. Bars are means ± SD of three independent experiments.</p