@article{DjuzenovaFiedlerMemmeletal.2019,
  author    = {Djuzenova, Cholpon S. and Fiedler, Vanessa and Memmel, Simon and Katzer, Astrid and Sisario, Dmitri and Brosch, Philippa K. and G{\"o}hrung, Alexander and Frister, Svenja and Zimmermann, Heiko and Flentje, Michael and Sukhorukov, Vladimir L.},
  title     = {Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells},
  series = {BMC Cancer},
  volume    = {19},
  journal   = {BMC Cancer},
  doi       = {10.1186/s12885-019-5517-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200290},
  pages     = {299},
  year      = {2019},
  abstract  = {Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. Results We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. Conclusions Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.},
  language  = {en}
}
@phdthesis{Awad2019,
  author    = {Awad, Eman Da'as},
  title     = {Modulation of insulin-induced genotoxicity in vitro and genomic damage in gestational diabetes},
  doi       = {10.25972/OPUS-16186},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161866},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Diabetes mellitus is a global health problem, where the risk of diabetes increases rapidly due to the lifestyle changes. Patients with type II diabetes have many complications with increased risk of morbidity and mortality. High levels of insulin may lead to DNA oxidation and damage. Several studies proposed that hyperinsulinemia may be an important risk factor for various types of cancer. To investigate insulin signaling pathway inducing oxidative stress and genomic damage, pharmaceutical and natural compounds which can interfere with the insulin pathway including PI3K inhibitors, resveratrol, lovastatin, and RAD-001 were selected due to their beneficial effects against metabolic disorder. Thus, the anti-genotoxic potential of these compounds regarding insulin-mediated oxidative stress were investigated in normal rat kidney cells in vitro. Our compounds showed protective effect against genotoxic damage and significantly decreased reactive oxygen specious after treatment of cells with insulin with different mechanisms of protection between the compounds. Thus, these compounds may be attractive candidates for future support of diabetes mellitus therapy. Next, we explored the link between gestational diabetes mellitus and genomic damage in cells derived from human blood. Moreover, we investigated the influence of estradiol, progesterone, adrenaline and triiodothyronine on insulin-induced genomic damage in vitro. First, we studied the effect of these hormones in human promyelocytic leukemia cells and next ex vivo with non-stimulated and stimulated peripheral blood mononuclear cells. In parallel, we also measured the basal genomic damage using three conditions (whole blood, non-stimulated and stimulated peripheral blood mononuclear cells) in a small patient study including non-pregnant controls with/without hormonal contraceptives, with a subgroup of obese women, pregnant women, and gestational diabetes affected women. A second-time point after delivery was also applied for analysis of the blood samples. Our results showed that GDM subjects and obese individuals exhibited higher basal DNA damage compared to lower weight nonpregnant or healthy pregnant women in stimulated peripheral blood mononuclear cells in both comet and micronucleus assays. On the other hand, the DNA damage in GDM women had decreased at two months after birth. Moreover, the applied hormones also showed an influence in vitro in the enhancement of the genomic damage in cells of the control and pregnant groups but this damage did not exceed the damage which existed in obese and gestational diabetes mellitus patients with high level of genomic damage. In conclusion, insulin can induce genomic damage in cultured cells, which can be modulated by pharmaceutical and naturals substances. This may be for future use in the protection of diabetic patients, who suffer from hyperinsulinemia during certain disease stages. A particular form of diabetes, GDM, was shown to lead to elevated DNA damage in affected women, which is reduced again after delivery. Cells of affected women do not show an enhanced, but rather a reduced sensitivity for further DNA damage induction by hormonal treatment in vitro. A potential reason may be an existence of a maximally inducible damage by hormonal influences.},
  subject      = {Gestationsdiabetes},
  language  = {en}
}