FP6 priority

1.1.1   Genomics and Biotechnology for Health

1.1.2

Title of the proposal

Overexpression of mdr1 – p-glycoprotein and multidrug resistance of neoplastic cells

Institute

Slovak Academy of sciences, Institute of Molecular Physiology and Genetics
Vlarska 5, 83334 Bratislava, Slovak Republic

Contact

Research subject for a potential FP6 project

Multidrug resistance (MDR) of neoplastic tissue represents phenomenon when neoplastic cells become resistant to the diverse groups of cytotoxic substances with unrelated chemical structure and mechanisms of pharmacological action. MDR should be considered as one of the major obstacle in the effective chemotherapy of neoplastic diseases. This cross-resistance of cells was often found to be accompanied with high over-expression of mdr1 gene encoded plasma membrane glycoprotein (170 kD, P-glycoprotein- PGP). PGP, the integral protein of plasma membrane, is member of ABC transporter family (efflux pumps) and in neoplastic MDR cells is responsible for elimination of lipophilic cytotoxic substances from intracellular space. Therefore, to found the way to inhibit the PGP efflux activity and consequently depress MDR represents crucial step in chemotherapy of neoplastic diseases with developed MDR of this type. PGP can be specifically regulated by influence of several substances ľ PGP inhibitors, which are finally depressing the MDR. These substances, named chemosensitizers, represent groups of diverse pharmacological substances, that involve the calcium entry blockers, inhibitors of calmodulin, local anesthetics [8] and some derivatives of xanthines. Mechanisms which are responsible for depression of MDR by chemosensitizers are not fully discovered, but may involve: i) direct interactions of chemosensitizers with PGP; ii) influence of chemosenzitizers on regulation of metabolism by second messengers like cAMP or calcium ions; iii) influence on the functions of calcium binding proteins. To search for drugs (very effective chemosensitizers) represent the main aim of this project.

Recent international cooperation of the research team

Proposer´s relevant publications related to the research subject

1. Barancik M., Bohacova V., Kvackajova J., Hudecova S., Krizanova O., Breier A.: SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur. J. Pharm. Sci. 14, (2001), 29-36
2. Breier A Drobna Z, Docolomansky P, Barancik M: Cytotoxic activity of several unrelated drugs on L1210 mouse leukemic cell sublines with P-glycoprotein (PGP) mediated multidrug resistance (MDR) phenotype. A QSAR study. Neoplasma 47 2000 100-106
3. Breier A, Drobna Z, Barancik M: Direct interaction between verapamil and doxorubicin causes the lack of reversal effect of verapamil on P-glycoprotein mediated resistance to doxorubicin in vitro using L1210/VCR cells. Neoplasma 45 (1998) 248-253