Leptin contributes to the protection of human leukemic cells from cisplatinum cytoxicity.
Leptin (ob gene) and its cognate receptor (obr) are relevant for fat metabolism. Obr shares homology with the IL-6 signal transducer gp130 and is expressed in hematopoietic cells. Since cytokines and growth factors regulate both hematopoiesis and response to chemotherapy, we tested the hypothesis of whether leptin protects leukemic cells from cytotoxicity of cisplatinum. Antisense phosphorothioate oligodeoxynucleotides (ODNs) and antisense peptide nucleic acids (PNAs) complementary to the obr gene were first tested for their growth inhibitory activity in obr expressing leukemic cells. Liposome-mediated transfection of ODNs (1-2 microM) or PNAs (0.01-1 microM) inhibited growth up to 50%. Combination treatments of cisplatinum and 0.01 microM PNA reduced growth more than cisplatinum alone. Vice versa, recombinant human leptin (rhL) diminished cisplatinum-induced growth inhibition. Finally, we investigated whether rhL affects cisplatinum-induced DNA damage and repair in the housekeeping gene beta-actin by means of real time TaqMan polymerase chain reaction. RhL reduced DNA damage and increased DNA repair. The effects are, however, modest and leptin is probably not the only player in the armory of growth factors which affect drug resistance.
Efferth
T
T
Hospital for Internal Medicine IV, RWTH Aachen, Germany. tseffert@viro.med.uni-erlangen.de
Fabry
U
U
Osieka
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020014:K562 Cells / Q000187:drug effects*; D020738:Leptin / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020738:Leptin; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D002945:Cisplatin