Effects of nontoxic heat shock protein 90 inhibitor peptide derivatives on reversal of MDR of tumor cells.
Novel heat shock protein 90 inhibitor peptide derivatives [D- Trp-Phe-D- Trp-Leu-AMB (1), p-HOPA-D- TrpPhe-D-Trp-Leu-psi(CH2NH)-Leu-NH2 (2), D-Trp-Phe-D-Trp-OH (3), Suc-D-Trp-Phe-D-Trp-Leu-AMB (4), D-Tyr-Phe-D-Trp-Leu-AMB (5), D-Arg-D-Trp-Phe-D-Trp-Leu-Leu-NH2 (6), Leu-psi(CH2NH)-Leu-NH2x2HCl (7), Phe-Trp-Phe-Trp-Leu-Leu-NH2 (8), Tyr-Trp-Phe-Trp-Leu-Leu-NH2 (9) and Tyr-D- Trp-Phe-D-Trp-Leu-Leu-NH2 (10)] were synthetized, and their ability to reverse multidrug resistance (MDR) was studied. Peptide derivatives 1, 4 and 5, with D-Trp or D-Tyr residues in the N-terminal position caused a marked inhibition of MDR in cancer cells. These MDR inhibitor compounds and epirubicin were demonstrated to have additive and synergistic antiproliferative effects in checkerboard experiments on human MDR1 gene-transfected mouse lymphoma cells in vitro. It is suggested that the MDR reversal effects of these anticancer peptide derivatives, together with their antiproliferative effects on lung cancer cells, may open up new horizons in cancer chemotherapy.
Molnár
Joseph
J
Department of Medical Microbiology and Immunobiology, Albert Szent-Györgyi Medical Center, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary. molnarj@comser.szote.u-szeged.hu
Engi
Helga
H
Mándi
Yvette
Y
Somlai
Csaba
C
Penke
Botond
B
Szabó
Andrea
A
Orosz
Antal
A
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007940:Leukemia L5178 / Q000188:drug therapy; D051379:Mice; D010446:Peptide Fragments / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D010446:Peptide Fragments