Mdm2 inhibitors as a platform for the design of P-glycoprotein inhibitors.

Chemoresistance is thought to be the cause of low treatment efficacy and mortality in more than 90% of patients with advanced cancer. The activation of drug efflux by P-glycoprotein is the key mechanism of resistance. All known P-gp inhibitors are used only in the combination therapy. We propose a new approach based on the multitarget rational design of drugs, which possess both the antitumor and efflux pump inhibitory activity. In this work, the principle possibility of combining the ability to inhibit P-gp and p53-Mdm2 protein-protein interaction in one structure is considered. The biological activity of a number of known and newly synthesized compounds was evaluated using cell lines with different p53 status. The possibility of using computer modeling for the search for P-glycoprotein inhibitors among Mdm2 inhibitors was analyzed; P-gp interaction site and binding modes of substrates and inhibitors were identified. The results obtained in cells that have the native balance of drug resistance and sensitivity showed the ability of the cells to both actively throw out xenobiotics and to lose this ability using P-gp inhibitors. The data obtained indicate that Mdm2 inhibitors are a promising platform for the development of multitarget drugs that can overcome tumor resistance by inhibiting the P-glycoprotein activity.

Discovery of Novel Isatin-Based p53 Inducers.

A series of isatin Schiff base derivatives were identified during in silico screening of the small molecule library for novel activators of p53. The compounds selected based on molecular docking results were further validated by a high-content screening assay using U2OS human osteosarcoma cells with an integrated EGFP-expressing p53-dependent reporter. The hit compounds activated and stabilized p53, as shown by Western blotting, at higher rates than the well-known positive control Nutlin-3. Thus, the p53-activating compounds identified by this approach represent useful molecular probes for various cancer studies.

[The role of mitochondrial dynamics in cell death].

Mitochondria are dynamic organelles whose homeostasis is defined by two opposite processes: fission (or fragmentation), or fusion. Fission of mitochondria results in generation of smaller organelles and fusion is when they produce tubular or net-like structures. Although a number of proteins are already known to control the process of fission/fusion additional regulators controlling these processes are being found. The Bcl-2 family members take part in the regulation of apoptosis and according to the current view are involved in the mitochondrial net-like structure maintenance. In this review we will discuss mechanisms of mitochondrial fission/fusion regulation and summarize the available information on the role of Bcl-2 family members in the regulation of mitochondrial fission/fusion dynamics.

AMP-activated protein kinase: structure, function, and role in pathological processes.

Recently, AMP-activated protein kinase (AMPK) has emerged as a key regulator of energy balance at cellular and whole-body levels. Due to the involvement in multiple signaling pathways, AMPK efficiently controls ATP-consuming/ATP-generating processes to maintain energy homeostasis under stress conditions. Loss of the kinase activity or attenuation of its expression leads to a variety of metabolic disorders and increases cancer risk. In this review, we discuss recent findings on the structure of AMPK, its activation mechanisms, as well as the consequences of its targets in regulation of metabolism. Particular attention is given to low-molecular-weight compounds that activate or inhibit AMPK; the perspective of therapeutic use of such modulators in treatment of several common diseases is discussed.

[The use of apoptosis inducers in the therapy of experimental influenza infection and preventing of chronic post-influenza lung damage].

Influenza is a respiratory infection widely spread around the world. Influenza complications are various in nature and in most cases involve the excessive proliferation of cells in respiratory tract as a factor of pathogenesis. In the present work the efficacy of the use of apoptosis inducer 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalenecarboxylic acid (AHPN) for prophylaxis of chronic damage on the stage of post- influenza pneumonia has been studied. Mice were infected with influenza virus A/mallard/Pennsylvania/10218/84(H5N2) with further study of the level of influenza virus reproduction in the lungs, specific mortality of animals and morphology of the foci of post-influenza pneumonia on the 15th day post inoculation. AHPN was shown to decrease the infectious activity of the virus in the lungs by 1.2-1.5 log10 EID50/0.2 mL depending on the dose as compared to the control group, in a weak decrease in mortality of animals (protection index was 12.5-37.5%). The application of AHPN restricted both the proliferative and infiltrative component in chronic post-influenza lesions. It demonstrated the most pronounced effect on the lung morphology when applied on days 4 to 7 post inoculation, i. e. in the period of maximal activation of inflammatory tissue infiltration and regeneration of bronchiolar epithelium. In conclusion, the use of apoptosis inducers can partially prevent the development of chronic post-influenza lesions with proliferative component.