Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 5-year survival rate of only 6%. Although the cytosine analog gemcitabine is the drug commonly used to treat PDAC, chemoresistance unfortunately renders the drug ineffective. Thus, strategies that can decrease this resistance will be essential for improving the dismal outcome of patients suffering from this disease. We previously observed that oncogenic Pim-1 kinase was aberrantly expressed in PDAC tissues and cell lines and was responsible for radioresistance. Furthermore, members of the Pim family have been shown to reduce the efficacy of chemotherapeutic drugs in cancer. Therefore, we attempted to evaluate the role of Pim-3 in chemoresistance of PDAC cells. We were able to confirm upregulation of the Pim-3 oncogene in PDAC tissues and cell lines versus normal samples. Biological consequences of inhibiting Pim-3 expression with shRNA-mediated suppression included decreases in anchorage-dependent growth, invasion through Matrigel and chemoresistance to gemcitabine as measured by caspase-3 activity. Additionally, we were able to demonstrate that Pim-1 and Pim-3 play overlapping but non-identical roles as it relates to gemcitabine sensitivity of pancreatic cancer cells. To further support the role of Pim-3 suppression in sensitizing PDAC cells to gemcitabine, we used the pharmacological Pim kinase inhibitor SGI-1776. Treatment of PDAC cells with SGI-1776 resulted in decreased phosphorylation of the proapoptotic protein Bad and cell cycle changes. When SGI-1776 was combined with gemcitabine, there was a greater decrease in cell viability in the PDAC cells versus cells treated with either of the drugs separately. These results suggest combining drug therapies that inhibit Pim kinases, such as Pim-3, with chemotherapeutic agents, to aid in decreasing chemoresistance in pancreatic cancer.
Optimum use of organic corrosion inhibitors in coatings requires a better understanding of their protective mechanisms, including their orientation on steel substrates. The molecular orientation of N-oleoylsarcosine on steel was determined by a combination of specular reflectance Fourier transform infrared spectroscopy, ellipsometry, and electron spectroscopy. Studies suggest that it functions as a corrosion inhibitor by forming a chelate with the steel surface.
Potential energy curves have been computed using SCF and CI techniques for ground and excited state interactions of H2 with H+2. A total of seven planar and two nonplanar interaction geometries have been studied. In all cases the H2 and H+2 bond lengths were restricted to their equilibrium values, while the intermolecular H2–H+2 distance varied from 0.5 to 12 a.u. Ground state binding energies were found to range from 0.4 to 1.6 eV in the SCF calculations and from 0.8 to 1.9 eV in the complete single-and-double excitation CI calculations (SD–CI). In both SCF and SD–CI calculations, the most stable geometry was found to be the perpendicular orientation, with the H+2 molecule lying on a line bisecting the H2 bond axis. Potential curves were also computed for the charge-transfer excited state of H2–H+2, and these results are discussed in terms of their implications for the dynamics of charge exchange reactions.
Energies of the 15 lowest Rydberg states of the metastable H4 cluster have been determined using Koopman's theorem at the equilibrium geometry of the parent ion, H4 +. To represent the core orbitals of H4, a 6-31G** basis set has been used at the SCF, MP2, MP4(SDTQ), CI-SD, and CI-SDT levels. The Rydberg orbitals have been modeled using a basis set analogous to that used to model the Rydberg orbitals of H3 in previous theoretical calculations. To test the validity of the calculations for the H4 molecule, ab initio calculations were repeated for the Rydberg orbitals of the H3 molecule at the stable geometry of the H3 + core. Predicted transitions were within 2% of the rotational band spectra of H3 observed by Herzberg. The metastable H4 cluster formed from charge neutralization of H4 + decomposes into two H2 molecules. Previous calculations have predicted that one of the two H2 products will be vibrationally hot while the other will be relatively cold and that a large recoil energy of approximately 9 eV is expected for the relative kinetic energy of the two H2 products. The present work suggests that if Rydberg states are involved in the charge neutralization process, the recoil energy could be reduced due to radiative transitions among the Rydberg states.
Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, making it the worse subtype of all breast cancers. Currently, there are no molecular targeted therapies for this cancer and chemotherapy is only successful in a limited number of patients. Recent studies suggest that members of the oncogenic PIM kinase family, especially PIM-1, play a significant role in the growth of TNBC. However, there is very limited information on the role other PIM family members have in the growth and development of TNBCs. As an attempt to address this concern, we treated a panel of TNBC cell lines with HS140, a PIM-2 kinase inhibitor developed in the laboratory. Using cytotoxicity assays, we were able to demonstrate a decrease in anchorage-dependent growth of cell lines at different concentrations of HS140. Also, a triple negative breast cancer GEMM (C3TAg) was used for an efficacy study. Mice (FVB/N background) have C(3)SV40 T-antigen resulting in inactivation of p53 and Rb. Nine mice received HS140 treatment (80mg/kg BIW IP) and 14 left untreated for control (non-treatment [NT]). All mice were monitored for weight loss and timespan to tumor development 5 times weekly. Tumor volumes at 21 days were significantly (Mann-Whitney, p=0.0002) reduced in the treated cohort with a mean of 109mm3 (range of 0-5000) compared to untreated 1393mm3 (0-239). We observed no toxicities with body mass stable at the treatment dose of 80mg/kg. Additionally, three mice from untreated and three mice from treated cohorts were chosen for blood sampling pre- and post-treatment via a submandibular bleed; no significant differences were noted in WBC, RBC, PLT, or HGB between untreated and treated cohorts. Overall, these results suggest that other members of the PIM kinase family, including PIM-2, have an important function in the growth and development of TNBC and may serve as a potential molecular target for future therapeutics. Citation Format: Michael Cobb, Lucas Hunter, David Carlson, David Darr, Timothy Haystead, Antonio T. Baines. Characterizing the in vitro and in vivo effects of the PIM kinase inhibitor HS140 in triple-negative human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 524. doi:10.1158/1538-7445.AM2017-524
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