Medical Radiology Research Center

Obninsk, Russia

Medical Radiology Research Center

Obninsk, Russia
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Proskuryakov S.Y.,Medical Radiology Research Center | Gabai V.L.,Boston University
Current Pharmaceutical Design | Year: 2010

Until recently, necrosis, unlike apoptosis, was considered as passive and unregulated form of cell death. However, during the last decade a number of experimental data demonstrated that, except under extreme conditions, necrosis may be a well-regulated process activated by rather specific physiological and pathological stimuli. In this review, we consider mechanisms and the role of necrosis in tumor cells. It became recently clear that the major player in necrotic cascade is a protein kinase RIP1, which can be activated by number of stumuli including TNF, TRAIL, and LPS, oxidative stress, or DNA damage (via poly-ADP-ribose polymerase). RIP1 kinase directly (or indirectly via another kinase JNK) transduces signal to mitochondria and causes specific damage (mitochondrial permeability transition). Mitochondrial collapse activates various proteases (e.g., calpains, cathepsin) and phospholipases, and eventually leads to plasma membrane destruction, a hallmark of necrotic cell death. Necrosis, in contrast to apoptosis, usually evokes powerful inflammatory response, which may participate in tumor regression during anticancer therapy. On the other hand, excessive spontaneous necrosis during tumor development may lead to more aggressive tumors due to stimulatory role of necrosis-induced inflammation on their growth. © 2010 Bentham Science Publishers Ltd.


Colvin T.A.,Boston University | Gabai V.L.,Boston University | Gong J.,Boston University | Calderwood S.K.,Beth Israel Deaconess Medical Center | And 13 more authors.
Cancer Research | Year: 2014

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target. © 2014 American Association for Cancer Research.


PubMed | University of Massachusetts Boston, Medical Radiology Research Center, University of California at San Francisco, Beth Israel Deaconess Medical Center and Molecular Therapeutics
Type: Journal Article | Journal: Cancer research | Year: 2014

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-B, FoxM1, Hif1, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.


Gorban N.A.,Medical Radiology Research Center | Kudaibergenova A.G.,The Surgical Center | Pankratov V.A.,Medical Radiology Research Center
Arkhiv Patologii | Year: 2013

Prognosis for patients with laryngeal squamous cell carcinoma depends on many factors, among which molecular biological markers receive ever increasing attention. The purpose of this study was to determine the prognostic value of the expression of the proteins p53 and bcl-2 and the proliferation markers Ki-67 and cyclin D1 in laryngeal squamous cell carcinoma. Biopsy specimens from 64 patients aged 34 to 77 years (mean age 56±1.2 years) with invasive laryngeal squamous cell carcinoma, who received combination therapy at the Medical Radiology Research Center, Russian Academy of Medical Sciences, were studied. The level of Ki-67 and the expression of cyclin D1, p53, and bcl-2 were compared with clinical and anatomic parameters (T stage, tumor grade, and the presence of regional metastases), using Student's (-test and fourfold table analysis (x2 or Fisher's exact test). Survival rates were analyzed by the Kaplan-Meier method; the significance of differences between survival curves was confirmed by Cox's F-test. The value p<0.05 was taken to be significant. Ki-67 is an important prognostic marker for the N status (p=0.03) and recurrence (p=0.04) and a marker for tumor grading (p<0.01). Cyclin D1 expression is associated with low overall and relapse-free survival rates (p=0.05 and 0.03, respectively). The prognostic marker for a recurrence is p53 (p=0.01) that is related to the N status at the trend level (p=0.08). The marker bcl-2 is associated with high overall survival (p=0.01) and N status at the trend level (p=0.08).


Abrosimov A.Yu.,Medical Radiology Research Center | Ryzhenkova M.I.,Medical Radiology Research Center
Arkhiv Patologii | Year: 2014

Papillary thyroid carcinoma is generally characterized by a favorable prognosis in patients after timely and adequate treatment. However, local tumor growth recurrences and regional and distant metastases may occur in 5-20% of cases posttreatment. Objective - to comparatively analyze the morphology and cellular composition of papillary thyroid carcinoma in two patient groups with comparable clinical and morphological characteristics, but different in the long-term results of treatment. Material and methods. Histological specimens from 17 papillary thyroid carcinoma cases with recurrent tumor growth after treatment and resurgery (an experimental group) and 18 control cases without recurrences were selected from the database of the Chernobyl bank. The morphological features of primary tumors were studied in both groups; the morphology of recurrent tumors was also investigated in the experimental group. Results. The higher incidence of tumors with papillary structure and a focal component from high-columnar, clear, and oxyphilic tumor cells was found in a group with a poor prognosis (a local relapse and metastases in the regional lymph nodes after thyroidectomy, hormonal and radioiodine therapy. Conclusion. The found morphological features of recurrent papillary thyroid carcinoma may serve as a starting point for further establishing criteria for tumor resistance to radioiodine therapy and for substantiating indications for other high-technology treatments, including targeted therapy.


Kudryavtsev V.A.,Medical Radiology Research Center | Makarova Yu.M.,Medical Radiology Research Center | Kabakov A.E.,Medical Radiology Research Center
Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry | Year: 2012

Effects of inhibitors of the heat shock protein 90 (HSP90) chaperone activity and inhibitors of the heat shock protein (HSP) expression on sensitivity of HeLa tumor cells to hyperthermia were studied. It was found that nanomolar concentrations of inhibitors of the HSP90 activity (17AAG or radicicol) slowed down the chaperone-dependent reactivation of a thermolabile reporter (luciferase) in heat-stressed HeLa cells and slightly enhanced their death following the incubation for 60 min at 43°C. The inhibitors of HSP90 activity stimulated de novo induction of additional chaperones (HSP70 and HSP27) that significantly increased intracellular HSP levels. Treatment of the cells with 17AAG or radicicol along with an inhibitor of the HSP induction (e.g. quercetin or triptolide, or NZ28) completely prevented the increase in the intracellular chaperone levels resulting from the inhibition of HSP90 activity and subsequent heating. Combination of all three treatments (inhibition of the HSP90 activity + inhibition of the HSP induction + heating at 43°C for 60 min) resulted in more potent inhibition of the reporter reactivation and a sharp (2-3-fold) increase in cell death. Such enhancement of the cytotoxicity may be attributed to the "chaperone deficiency" when prior to heat stress both the functional activity of constitutive HSP90 and the expression of additional (inducible) chaperones are blocked in the cells. © Pleiades Publishing, Ltd., 2012.


Kabakov A.E.,Medical Radiology Research Center | Kudryavtsev V.A.,Medical Radiology Research Center | Gabai V.L.,Boston University
Journal of Molecular Medicine | Year: 2010

The 90-kD heat shock protein (Hsp90) is an abundant molecular chaperone catalyzing maturation and activation of client proteins. A number of the Hsp90 client proteins are components of cancer cell-associated signaling pathways that ensure unlimited growth of tumors and their resistance to chemotherapy and radiotherapy. Upon inhibition of the Hsp90 chaperone function, such client proteins are destabilized and degraded which disrupts multiple pathways essential for tumor cell survival; hence, pharmacological Hsp90 inhibitors could be applied in anticancer therapy. Several Hsp90-inhibiting compounds are currently tested in preclinical or phase I-III clinical trials as single anticancer agents or in combination with conventional drugs and radiation. The present review summarizes the data characterizing Hsp90 inhibitors as agents that sensitize human tumors to irradiation which may improve the outcome of radiotherapy. We also discuss molecular mechanisms of the Hsp90 inhibition-induced radiosensitization and its selectivity toward cancer cells. © 2009 Springer-Verlag.


Kabakov A.E.,Medical Radiology Research Center | Kudryavtsev V.A.,Medical Radiology Research Center | Gabai V.L.,Boston University
Methods in Molecular Biology | Year: 2011

Cell death (in particular, apoptosis and necrosis) is accompanied by appearance of certain hallmarks that are manifested as specific alterations in cellular membranes, cytoplasm, nucleus and mitochondria. Some of those hallmarks are easily detectable in situ and, therefore, they can be applied for the assessment of dying or dead cells. In turn, there are also signs of viable cells that include a set of features, such as normal functioning of their membranes and organelles, ability to proliferate, etc. The present chapter provides descriptions of several convenient methods for quantitative determination of dead (apoptotic and necrotic) cells and also methods for determination of survived and viable cells. Here, we describe in details the methods of annexin V/propidium iodide (PI) staining, TUNEL assay, Hoechst/PI staining, MTS tetrazolium assay, and colony formation assay, with the principles, advantages, and drawbacks of each technique. © 2011 Springer Science+Business Media, LLC.


Kabakov A.E.,Medical Radiology Research Center | Kudryavtsev V.A.,Medical Radiology Research Center
Current Topics in Pharmacology | Year: 2010

In vivo, heat shock protein 90 (Hsp90) functions as an ATP-dependent chaperone catalyzing maturation and activation of client proteins. A number of its client proteins are implicated in cancer-associated pathways that ensure tumor growth and resistance to therapeutics; in the case of Hsp90 dysfunction, these proteins are destabilized and degraded thus impairing the proliferative/defensive potential of cancer cells. Consequently, suitable inhibitors of Hsp90 could be applied as effective anticancer agents. Two low-toxic analogues of Geldanamycin, 17-N-allilamino-17-demethoxygeldanamycin (17AAG) and 17-N-dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG), are the Hsp90 inhibitors which exhibited prominent anticancer activity in many oncology-relevant models and primary clinical trials. It was found that clinically achievable concentrations of these drugs can kill or repress cells of human leukemia and some solid tumors. Moreover, 17AAG and 17DMAG are able to sensitize malignancies to other chemotherapeutic drugs, radiotherapy and immunotherapy. The most optimistic prospects are based on the fact that Hsp90 in cancer cells binds 17AAG with ∼100-fold higher affinity than Hsp90 in normal cells. Such a difference suggests that in the patient's organism the drug will preferentially target malignant cells and the drug-induced cytotoxicity will be localized within tumors. In addition, 17AAG and 17DMAG were shown to suppress the vascularization, invasiveness and metastasing of tumors. The present review generalizes numerous data on anticancer effects of the Hsp90 inhibitors and affords insight into molecular machinery of those effects. Potential trends and problems in the application of Hsp90 inhibitors to cancer treatment are also discussed.


Abrosimov A.Yu.,Medical Radiology Research Center | Shinkarkina A.P.,Medical Radiology Research Center
Arkhiv Patologii | Year: 2013

The paper describes a rare case of concurrent two different histological (follicular and columnar cell) variants of papillary carcinoma in one thyroid with columnar cell metastases to the lymph nodes and femoral bone. There are morphological features of and differences in BRAF status in the cells of two variants of papillary thyroid carcinoma.

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