Transferrin as a drug carrier: Cytotoxicity, cellular uptake and transport kinetics of doxorubicin transferrin conjugate in the human leukemia cells (original) (raw)

2014, Toxicology in Vitro

Leukemias are one of most common malignancies worldwide. There is a substantial need for new chemo-33 therapeutic drugs effective against this cancer. Doxorubicin (DOX), used for treatment of leukemias and 34 solid tumors, is poorly efficacious when it is administered systemically at conventional doses. Therefore, 35 several strategies have been developed to reduce the side effects of this anthracycline treatment. In this 36 study we compared the effect of DOX and doxorubicin-transferrin conjugate (DOX-TRF) on human leu-37 kemia cell lines: chronic erythromyeloblastoid leukemia (K562), sensitive and resistant (K562/DOX) to 38 doxorubicin, and acute lymphoblastic leukemia (CCRF-CEM). Experiments were also carried out on nor-39 mal cells, peripheral blood mononuclear cells (PBMC). We analyzed the chemical structure of DOX-TRF 40 conjugate by using mass spectroscopy. The in vitro growth-inhibition assay XTT, indicated that DOX-TRF 41 is more cytotoxic for leukemia cells sensitive and resistant to doxorubicin and significantly less sensitive 42 to normal cells compared to DOX alone. During the assessment of intracellular DOX-TRF accumulation it 43 was confirmed that the tested malignant cells were able to retain the examined conjugate for longer peri-44 ods of time than normal lymphocytes. Comparison of kinetic parameters showed that the rate of DOX-45 TRF efflux was also slower in the tested cells than free DOX. The results presented here should contribute 46 to the understanding of the differences in antitumor activities of the DOX-TRF conjugate and free drug. 47 48 49 60 carried out to improve the chemotherapeutic potency of doxorubi-61 cin and other anthracyclines (Luo et al., 2011; Salvatorelli et al., 62 2012). The goal of anticancer drug development is to identify 63 agents that are effective cancer medicines and yet have minimal 64 systemic side effects. A way to improve the selectivity of cancer 65 therapy is to direct drug activity against therapeutic targets that 66 display altered levels of expression in malignant versus normal 67 cells (Kratz et al., 2008). The use of drug carriers, such as liposomes, 68 dendrimers, nanoparticles, antibodies and others may be part of 69 this approach in allowing increased intracellular concentrations 70 of the cytotoxic agents in cancer cells, therefore helping to over-71 come the chemoresistance of neoplastic cells (Haag and Kratz, 72 2006). 73 Effective and selective anticancer drug carriers are protein con-74 jugates of anthracyclines. Transferrin (TRF) is a plasma protein that 75 can be used as a carrier of anthracyclines because receptors for this 76 protein are overexpressed at the surface of cancer cells, due to the 77 high demand of tumor cells for iron ions, which participate in 78 energy production, heme synthesis, and cell proliferation