Synthesis of daunomycin-oligoarginine conjugates and their effect on human leukemia cells (HL-60)

Bánóczi, Zoltán; Peregi, Balázs; Orbán, Erika; Szabó, Rita; Hudecz, Ferenc

doi:10.3998/ark.5550190.0009.313

Cited by 20 publications

(13 citation statements)

References 19 publications

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“…All conjugates were active and resulted in cytostatic effect on all of the cells (Table 3). In case of HL-60 cells the cytostatic activity is comparable with hexaand octaarginine-containing conjugates (Bánóczi et al 2008b). The conjugates of tetra-and hexaarginine derivatives showed similar activity on both breast cancer cells (MCF-7 and MDA-MB-231).…”

Section: Cytostatic Activity Of Conjugates Containing Antitumor Drug and Dabcyl-arg 6 -Lys-nhmentioning

confidence: 80%

“…Octaarginine as a well-known CPP is frequently used to deliver wide range of cargos (e.g. small drug molecules (Miklán et al 2007(Miklán et al , 2011Bánóczi et al 2008bBánóczi et al , 2010Bánóczi et al , 2018, and peptides into cells (Bánoczi et al 2007;Bánóczi et al 2008a;Szabó et al 2016). In some cases it is failed to deliver efficiently the cargo into the cells, thus their biological activity was poor; for example in case of methotrexate and its pentaglutamylated derivative (Szabó et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Influence of the Dabcyl group on the cellular uptake of cationic peptides: short oligoarginines as efficient cell-penetrating peptides

et al. 2021

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Cell-penetrating peptides (CPPs) are promising delivery vehicles. These short peptides can transport wide range of cargos into cells, although their usage has often limitations. One of them is the endosomatic internalisation and thus the vesicular entrapment. Modifications which increases the direct delivery into the cytosol is highly researched area. Among the oligoarginines the longer ones (n > 6) show efficient internalisation and they are well-known members of CPPs. Herein, we describe the modification of tetra- and hexaarginine with (4–((4–(dimethylamino)phenyl)azo)benzoyl) (Dabcyl) group. This chromophore, which is often used in FRET system increased the internalisation of both peptides, and its effect was more outstanding in case of hexaarginine. The modified hexaarginine may enter into cells more effectively than octaarginine, and showed diffuse distribution besides vesicular transport already at low concentration. The attachment of Dabcyl group not only increases the cellular uptake of the cell-penetrating peptides but it may affect the mechanism of their internalisation. Their conjugates with antitumor drugs were studied on different cells and showed antitumor activity.

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Section: Cytostatic Activity Of Conjugates Containing Antitumor Drug and Dabcyl-arg 6 -Lys-nhmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Influence of the Dabcyl group on the cellular uptake of cationic peptides: short oligoarginines as efficient cell-penetrating peptides

et al. 2021

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“…This strategy has recently been employed for the coupling of daunomycin to triplex forming oligonucleotides. 26 Peptide conjugates of daunomycin were synthesized for various purposes: to reduce its side effects; 23 to circumvent the multidrug resistance; 27,28 and to increase the selectivity or target the molecule to a specific part of the body. 21,29−31 It was found that the nature of the chemical bond between daunomycin and the peptide could markedly influence the chemical and biological properties of the conjugate and, thus, the efficacy of the drug.…”

Section: ■ Introductionmentioning

confidence: 99%

A New Daunomycin–Peptide Conjugate: Synthesis, Characterization and the Effect on the Protein Expression Profile of HL-60 Cells in Vitro

et al. 2011

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Daunomycin (Dau) is a DNA-binding antineoplastic agent in the treatment of various types of cancer, such as osteosarcomas and acute myeloid leukemia. One approach to improve its selectivity and to decrease the side effects is the conjugation of Dau with oligopeptide carriers, which might alter the drug uptake and intracellular fate. Here, we report on the synthesis, characterization, and in vitro biological properties of a novel conjugate in which Dau is attached, via an oxime bond, to one of the cancer specific small peptides (LTVSPWY) selected from a random phage peptide library. The in vitro cytostatic effect and cellular uptake of Dau═Aoa-LTVSPWY-NH(2) conjugate were studied on various human cancer cell lines expressing different levels of ErbB2 receptor which could be targeted by the peptide. We found that the new daunomycin-peptide conjugate is highly cytostatic and could be taken up efficiently by the human cancer cells studied. However, the conjugate was less effective than the free drug itself. RP-HPLC data indicate that the conjugate is stable at least for 24 h in the pH 2.5-7.0 range of buffers, as well as in cell culture medium. The conjugate in the presence of rat liver lysosomal homogenate, as indicated by LC-MS analysis, could be degraded. The smallest, Dau-containing metabolite (Dau═Aoa-Leu-OH) identified and prepared expresses DNA-binding ability. In order to get insight on the potential mechanism of action, we compared the protein expression profile of HL-60 human leukemia cells after treatment with the free and peptide conjugated daunomycin. Proteomic analysis suggests that the expression of several proteins has been altered. This includes three proteins, whose expression was lower (tubulin β chain) or markedly higher (proliferating cell nuclear antigen and protein kinase C inhibitor protein 1) after administration of cells with Dau-conjugate vs free drug.

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“…It is worth to note that MDA‐MB‐231 cells lack estrogen, progesterone and HER2 receptors, making them more resistant to some drugs [67] . These drugs were used earlier in conjugates of octarginine and penetratin, [23,68] thus we included them as a proof of concept, which has enabled us to learn about the enhanced activity influenced by the CPPs. On MCF‐7, the conjugates had modest IC 50 values (Dabcyl‐RRWRR(MTX) 46.3, Dabcyl‐WRRRRK(MTX) 36.9 μM) for MTX containing conjugates.…”

Section: Resultsmentioning

confidence: 99%

Modification of Short Non‐Permeable Peptides to Increase Cellular Uptake and Cytostatic Activity of Their Conjugates

et al. 2021

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Cell‐penetrating peptides (CPPs) are well‐known delivery vectors, oligoarginines are an important class of CPPs, which was modified to increase the cellular uptake and change the internalization mechanism. A minimum number of four Arg residues was used and tetrarginine sequence was modified by 4‐((4‐(dimethylamino)phenyl)azo)benzoic acid (Dabcyl) and Trp(s). The Dabcyl group was attached to the N‐terminus, while peptides were different in the number and position of Trp in their sequence. Their internalization was studied on breast cancer cells (MCF‐7 and MDA‐MB‐231), and Chinese hamster ovary cells (CHO) using different fluorescence techniques. Our most active CPPs, Dabcyl‐RRWRRK and Dabcyl‐WRRRRK were conjugated to antitumor drugs, resulting in considerable cytostatic activity, especially on MDA‐MB‐231 cell lines. These newly developed cell‐penetrating tetrarginine derivatives may enter cells very efficiently, mainly by direct translocation and caveolae‐mediated endocytosis, thus they may be promising delivery vehicle. Tetragrinines are considered inefficient CPPs, but with our modifications, we rendered them effective.

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Synthesis of daunomycin-oligoarginine conjugates and their effect on human leukemia cells (HL-60)

Cited by 20 publications

References 19 publications

Influence of the Dabcyl group on the cellular uptake of cationic peptides: short oligoarginines as efficient cell-penetrating peptides

Influence of the Dabcyl group on the cellular uptake of cationic peptides: short oligoarginines as efficient cell-penetrating peptides

A New Daunomycin–Peptide Conjugate: Synthesis, Characterization and the Effect on the Protein Expression Profile of HL-60 Cells in Vitro

Modification of Short Non‐Permeable Peptides to Increase Cellular Uptake and Cytostatic Activity of Their Conjugates

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