AbstractHyperthermia enhances the anticancer effects of thymidylate synthase (TYMS) inhibitors (raltitrexed, RTX) and improves the precise biochemical mechanisms partially through enhancement of intracellular drug absorption. Recent research focuses on the potential anticancer drug target Heat Shock Protein 90 (HSP90), which could increase the sensitivity of cancer cells to TYMS inhibitors; however, with different HSP90 inhibitors, several research studies finally showed a poor efficacy in preclinical or clinical research. Here, we showed that 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG, HSP90 inhibitor) affects the efficacy of chemotherapy through antioxidant activation–induced resistance. In this study, we found that RTX, alone or in combination with hyperthermia, triggers reactive oxygen species (ROS) exposure and thus induces cell death. Also, the addition of hyperthermia showed more ROS exposure and function. The pharmacologic inhibition of HSP90 reversed the effects of chemotherapeutical treatments, while the overexpression of HSP90 showed no relation with these effects, which demonstrated that dysregulation of HSP90 might have a significant impact on chemotherapeutic treatments. The addition of 17‐AAG increased the activation of antioxidant with increased antioxidant enzymes, thus affecting the RTX efficacy.

2014-11-01·Molecular Pharmacology3区 · 医学

In Silico Identification of an Aryl Hydrocarbon Receptor Antagonist with Biological Activity In Vitro and In Vivo

3区 · 医学

Article

作者: Haigh, Sarah E ; Schlezinger, Jennifer J ; Hahn, Mark E ; Hopper, Timothy G ; Parks, Ashley J ; Ashton, Trent D ; Vajda, Sandor ; Narasimhan, Supraja ; Beglov, Dimitri ; Kozakov, Dmytro ; Novikov, Olga ; Sherr, David H ; Pollastri, Michael P ; Stanford, Elizabeth A ; Franks, Diana G

The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand-induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)- and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration experiments, and AHR localization studies were consistent with competitive antagonism and blockade of nuclear translocation as the primary mechanism of action. CB7993113 (IC50 3.3 × 10(-7) M) effectively reduced invasion of human breast cancer cells in three-dimensional cultures and blocked tumor cell migration in two-dimensional cultures without significantly affecting cell viability or proliferation. Finally, CB7993113 effectively inhibited the bone marrow ablative effects of 7,12-dimethylbenz[a]anthracene in vivo, demonstrating drug absorption and tissue distribution leading to pharmacological efficacy. These experiments suggest that AHR antagonists such as CB7993113 may represent a new class of targeted therapeutics for immunomodulation and/or cancer therapy.

Wiadomosci lekarskie (Warsaw, Poland : 1960)

Research of the protection actions of derived 2-oxoindole in acute stress.

Article

作者: Vlasova, Elena V ; Lutsenko, Ruslan V ; Vakhnenko, Andrei V

INTRODUCTIONCorrection of pathological anxiety and stress level of frustration leads to the development of new anxiolytics, notably including derivatives of 2-oksoyndolyn- 3-hlyoksylic acid. The aim of work - to study the effect of 2-oksyindolin-3-hlyoksylic acid on emotional and behavioral reactions of rats subjected to behavioral stress tests of different averiability.MATERIALS AND METHODSIn experiments on 150 white mature male rats Wistar investigated the effects of 2-oksoindolin (2-hydroxy-N-naphthalene-1-yl-2-(2-hydroxy-1,2- dihydro-indole-3-ylidene)-acetamide) with laboratory codes 18 when intraperitoneally administered to acute immobilization stress on Sel'ye on emotional and behavioral responses of animals to test «open field», «a raised cross maze» and test «conflict behavior» (option Vogel).RESULTSEstablished that the prophylactic use of the compound 18 in a test of "open field" warned the stress changes in the latent period of the first movement, likely increased the number of exits to the center installation, warned breach vertical and horizontal motor activity and significantly increased the number of acts of grooming and reduced the number of boluses compared with stress without correction. Revealed changes suggest that the substance 18 prevents anxiety disorders conduct stress genesis. In the test «a raised cross maze» of 2-oksoindolin significantly increased the number of outputs rats in open arms maze and reduced the number of fecal balls compared with those in the control disorders. In the study antyconflict action found that the compound increased the number of approaches to the drinkers, but the activity in this test yielded diazepam.CONCLUSIONInstalled conservation action anksyolityc 2-hydroxy-N-naphthalene-1-yl-2-(2-hydroxy-1,2-dihydro-indole-3-ylidene)-atsetamidu acute stress may be associated with indirect stimulation of GABA - benzdiazepin receptor complex, by strengthening endogenous GABA affinity to the receptors and/or indirect stimulation of GABA receptors by other neurotransmitter systems, including serotonergic, which makes compounds for further study the possibility of post stress with anxiety disorders.

100 项与 TYMS inhibitors(Università degli Studi di Perugia) 相关的药物交易

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