FP6 priority

1.1.1   Genomics and Biotechnology for Health

1.1.1 Advanced genomics and its applications for health

Title of the proposal

Apoptosis and its modulation

Institute

Slovak Academy of Sciences, Cancer Research Institute
Vlarska 7, 833 91 Bratislava, Slovak Republic

Contact

Research subject for a potential FP6 project

The project is aimed at the study of:
I. - viability, immunophenotype, cell cycle and the relationship of these changes to programmed cell death (expression anti- and proapoptotic proteins) in human multidrug resistant leukemia and cacinoma (ovarian, breast) cells expressing MDR-1 gene coded for P-glycoprotein and MRP gene coded for p190 glycoprotein after induction with:
a/ anticancer drugs (taxanes, anthracyclins) ,
b/ vitamins (vitamin D3)
c/ retinoids (all-trans retinoic acid, 9-cis-retinoid acid, 13-cis-retinoid acid),
d/ inhibitors of histone deacetylase (trichostatin A, trapoxin A),
e/ platinum complexes (cisplatin, carboplatin),
epidophilotoxins (etoposide),
f/ modulators of multidrug resistance (inhibitors of protein kinases (staurosporine, N-benzoylstaurosporine CGP 41251, genistein), calcium channel blockers (verapamil), agonists of calmodulin (R24571), antiestrogens (tamoxifen), nonimmu-nosuppressive substances (SDZ-PSC 833), neuroleptics (ligand of peripheral benzodiazepine receptor PK11195).
II. - cell cycle and expression of MMR (mismatch-repair) proteins (hMLH1, hMSH2, HMSH6..) in human tumor MMR-deficient- and proficient tumor cells (lymphoblastoid, colon carcinoma, ovarian carcinoma) after induction with antimetabolite agents (6-thioguanine), methylating agents (temozolomide), anthracyclins (doxorubicin), platinum complexes (cis- and carboplatin), epidophylotoxins (etoposide) and potential apoptotic cell attributes monitored by the expression of anti- and proapoptotic proteins.

Recent international cooperation of the research team

Prof. R. Zeillinger, University of Vienna, Department of Obstetrics and Gynecology,Molecular Oncology Group, Vienna, Austria; Prof. T. Szekeres, Klinisches Institut f. Med. & Chem. Labordiagnostik AKH-Wien, Vienna, AustriaProf. Vincent Castronovo, Metastasis Research Laboratory, University of Liege, Sart-Tilman, Liege, Belgium

Proposer´s relevant publications related to the research subject

1.HUNAKOVA L., SEDLAK J., KLOBUSICKA M., DURAJ J., CHORVATH B.: Tyrosine kinase inhibitor-induced differentiation of K-562 cells: alterations of cell cycle and cell surface phenotype. Cancer Lett., 81, 1994, 81-87.
2. DURAJ J., KOVACIKOVA M., SEDLAK J., KOPPEL J., SOBEL A., CHORVATH B.: Phosphorylation of stathmin during TPA-induced growth inhibition of human pre-B leukemia REH6 cells. Leukemia Res., 19, 1995, 457-461.
3. SEDLAK J., HUNAKOVA L., SULIKOVA M., CHORVATH B.: Protein kinase inhibitor-induced alterations of drug uptake, cell cycle and surface antigen expression in human multidrug-resistant (Pgp and MRP) promyelocytic leukemia (HL-60) cells. Leukemia Res., 21, 1997, 449-458.
4. CHORVATH B., SEDLAK J., NOVOTNY L., HUNAKOVA L., SEVCIKOVA L., BOLJESIKOVA E., CHORVATH M.: Non-immunosuppressive cyclosporine derivative PSC 833 abolishes the resistance of human multidrug-resistant ovarian carcinoma cells in vitro to paclitaxel and paclitaxel-induced radiosensitisation . Int. J. Cancer, 72, 1997, 916-917.
5. SEDLAK J., HUNAKOVA L., CHORVATH M., SULIKOVA M., NOVOTNY L., BOLJESIKOVA E., ZEILLINGER R., CHORVATH B.: Resistance of human multidrug-resistant neoplastic cell lines to paclitaxel-induced radiosensitization is reduced by the non-immunosuppressive cyclosporine analog SDZ PSC 833. Anticancer Res., 16, 1998, 3099-3106.
6. SEDLAK J., HUNAKOVA L., CHORVATH M., SULIKOVA M., NOVOTNY L., BOLJESIKOVA E., ZEILLINGER R., CHORVATH B.: Resistance of human multidrug-resistant neoplastic cell lines to paclitaxel-induced-radio-sensitization is reduced by the non-immunosuppressive cyclosporine analog SDZ PSC 833. Anticancer Res. 18, 1998, 3099-105.
7. SEDLAK J., HUNAKOVA L., DURAJ J., SULIKOVA M., CHOVANCOVA J., NOVOTNY L., CHORVATH B.: Detection of apoptosis in a heterogenous cell population using flow cytometry. Gen Physiol Biophys. 18, 1999, 147-54.
8. HUNAKOVA L., BIES J., SEDLAK J., DURAJ J., JAKUBIKOVA J., TAKACSOVA X., NOVOTNY L.,. CHORVATH B: Differential sensitivity of ovarian carcinoma cell lines to apoptosis induced by the IMPDH inhibitor benzamide riboside. Neoplasma 47, 2000, 274-9