Toxicity of doxorubicin-transferrin conjugate is connected to the modulation of Wnt/β-catenin pathway in human leukemia cells.
Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells caused by constitutive activation of the BCR/ABL tyrosine kinase. However, the tyrosine kinase inhibitors like imatinib mesylate are not effective in the patients with advanced-stage of CML. Hence, there is an urgent need for new approaches to overcome a cancer cell's resistance in CML long term therapy. Development of new drug carriers, is presently one of the most challenging tasks in experimental oncology. In this report we investigated whether the toxicity of newly synthetized doxorubicin transferrin conjugate (DOX-TRF) may be connected to the limitation of multidrug resistance in CML cells by the alternations of Wnt/β-catenin signaling pathway. The studies were performed on human chronic myeloid leukemia cell lines sensitive (K562) and resistant (K562/DOX) to doxorubicin. Our research proves that DOX-TRF conjugate displays higher cytotoxicity toward both examined cell lines than the reference free drug (DOX) and induces more extensive pro-apoptotic changes. Moreover, by the of engagement of Wnt pathway agonist (LiCl) and antagonist (ICG 001) we demonstrate that DOX-TRF conjugate effectively reduces transcription of key genes involved in β-catenin signaling transduction trial (Wnt3a, DVL-1, FZD-3, LRP5, β-catenin, DKK2) and triggers morphology alternations of CML cells.
Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland. Electronic address: szwedma@biol.uni.lodz.pl.
Marzena
M
Szwed
Laboratory of Transcriptional Regulation, Institute for Medical Biology, PAS, Lodowa 106 Street, 93-232 Lodz, Poland.
Katarzyna D
KD
Kania
Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland.
Zofia
Z
Jozwiak
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014168:Transferrin / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; D004337:Drug Carriers; D014168:Transferrin; D051176:beta Catenin; C000599870:doxorubicin-transferrin conjugate; D004317:Doxorubicin
DOX-TRF conjugate; Drug carriers; Leukemia cells; Wnt pathway