Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-D-arabinofuranosylcytosine in Daudi lymphoma cells

Abstract

Summary Low density lipoprotein (LDL) receptor-mediated uptake and cytotoxic effects of N 4 -octadecyl-1-β-D-arabinofuranosylcytosine (NOAC) were studied in Daudi lymphoma cells. NOAC was either incorporated into LDL or liposomes to compare specific and unspecific uptake mechanisms. Binding of LDL to Daudi cells was not altered after NOAC incorporation (K D 60 nM). Binding of liposomal NOAC was not saturable with increasing concentrations. Specific binding of NOAC-LDL to Daudi cells was five times higher than to human lymphocytes. LDL receptor binding could be blocked and up-or down-regulated. Co-incubation with colchicine reduced NOAC-LDL uptake by 36%. These results suggested that NOAC-LDL is taken up via the LDL receptor pathway. In an in vitro cytotoxicity test, the IC 50 of NOAC-LDL was about 160 µM, whereas with liposomal NOAC the IC 50 was 40 µM. Blocking the LDL receptors with empty LDL protected 50% of the cells from NOAC cytotoxicity. The cellular distribution of NOAC-LDL or NOAC-liposomes differed only in the membrane and nuclei fraction with 13% and 6% respectively. Although it is more convenient to prepare NOAC-liposomes as compared to the loading of LDL particles with the drug, the receptor-mediated uptake of NOAC-LDL provides an interesting rationale for the specific delivery of the drug to tumours that express elevated numbers of LDL receptors.

Antitumor Activity of Liposomal Naphthoquinone Esters Isolated from Thai Medicinal Plant: Rhinacanthus nasutus KURZ.

“…33) Furthermore, it is possible that rhinacanthins transferred to serum lipoprotein effectively accumulated in tumor tissues, since lipoproteins, especially low density lipoproteins, are known to deliver hydrophobic materials to tumor cells. [33][34][35][36] In the present study, the results demonstrated for the first time that rhinacanthins-N, -Q and -C entrapped in liposomes showed antiproliferative activities against HeLaS3 cells: The activities were slightly higher than that of free drugs after 24-and 48-exposure. Corresponding to the in vitro data, these liposomal drugs effectively suppressed tumor growth and increased the survival of Meth-A sarcoma-bearing BALB/c mice.…”

Evaluation of protein change and oxidative stress index after photodynamic therapy of corneal neovascularization

“…MA), is being used clinically in photodynamic therapy for age-related macular degeneration (Ichikawa 2004). Verteporfin is transported in the plasma primarily by lipoproteins (especially low-density lipoproteins), are known to deliver hydrophobic materials to tumor cells (de Smidt et al 1993;Koller-Lucae et al 1999;Pan et al 2004).…”

Human prostate cancer cells lack feedback regulation of low-density lipoprotein receptor and its regulator, SREBP2

“…Although the cancer cells benefit from loss of LDLR feedback regulation for their growth, it is possible to use this phenomenon in cancer therapy. Koller-Lucae et al 25 reported that an anti-cancer drug, N 4 -octadecyl-1-␤-D-arabinofuranosylcytosine, can be incorporated into LDL and taken up by lymphoma cells via the LDLR pathway. Because the normal cells express lower levels of LDLR than the cancer cells, especially after being feedback regulated by a high level of sterol, anti-cancer drugs carried by LDL may target more specifically and more efficiently FIGURE 3 -Cholesterol regulation of SREBP and LDLR expression.…”