Transferrin as a drug carrier: Cytotoxicity, cellular uptake and transport kinetics of doxorubicin transferrin conjugate in the human leukemia cells.
Leukemias are one of most common malignancies worldwide. There is a substantial need for new chemotherapeutic drugs effective against this cancer. Doxorubicin (DOX), used for treatment of leukemias and solid tumors, is poorly efficacious when it is administered systemically at conventional doses. Therefore, several strategies have been developed to reduce the side effects of this anthracycline treatment. In this study we compared the effect of DOX and doxorubicin-transferrin conjugate (DOX-TRF) on human leukemia cell lines: chronic erythromyeloblastoid leukemia (K562), sensitive and resistant (K562/DOX) to doxorubicin, and acute lymphoblastic leukemia (CCRF-CEM). Experiments were also carried out on normal cells, peripheral blood mononuclear cells (PBMC). We analyzed the chemical structure of DOX-TRF conjugate by using mass spectroscopy. The in vitro growth-inhibition assay XTT, indicated that DOX-TRF is more cytotoxic for leukemia cells sensitive and resistant to doxorubicin and significantly less sensitive to normal cells compared to DOX alone. During the assessment of intracellular DOX-TRF accumulation it was confirmed that the tested malignant cells were able to retain the examined conjugate for longer periods of time than normal lymphocytes. Comparison of kinetic parameters showed that the rate of DOX-TRF efflux was also slower in the tested cells than free DOX. The results presented here should contribute to the understanding of the differences in antitumor activities of the DOX-TRF conjugate and free drug.
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
Department of Immunology and Infectious Biology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16 Street, 90-237 Lodz, Poland.
Agnieszka
A
Matusiak
INSERM U916, Institut Bergonié, Université Bordeaux Segalen, 33076 Bordeaux, France.
Audrey
A
Laroche-Clary
INSERM U916, Institut Bergonié, Université Bordeaux Segalen, 33076 Bordeaux, France.
Jacques
J
Robert
Department of Biophysics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland.
Ilona
I
Marszalek
Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143 Street, 90-236 Lodz, Poland.
Zofia
Z
Jozwiak
D000465:Algorithms; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000633:toxicity*; D001693:Biological Transport, Active; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000633:toxicity*; D004337:Drug Carriers / Q000737:chemistry*; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013778:Tetrazolium Salts; D013844:Thiazoles; D014168:Transferrin / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*
D000903:Antibiotics, Antineoplastic; D004396:Coloring Agents; D004337:Drug Carriers; D013778:Tetrazolium Salts; D013844:Thiazoles; D014168:Transferrin; D004317:Doxorubicin; C022616:thiazolyl blue
CCRF-CEM; Cytotoxicity; DOX; DOX–TRF; Doxorubicin (DOX); Doxorubicin–transferrin conjugate (DOX–TRF); E(t)(=60); IMS; Intracellular drug accumulation; Ion Mobility Mass Spectrometry; K562; Leukemia cells; PBMC; TRF; U(t)(=60); V(in); V(out); acute lymphoblastic leukemia cells; chronic erythromyeloblastoid leukemia cells; collisional cross section; doxorubicin; doxorubicin–transferrin conjugate; drift times; drug removed by cells within 60min; drug taken up by cells within 60min; efflux rate; efflux rate constant; influx rate; influx rate constant; k(in); k(out); peripheral blood mononuclear cells; tD; transferrin; Ω