The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell-penetrating peptide

Bánóczi, Zoltán and Keglevich, András and Szabó, Ildikó and Ranđelović, Ivan and Hegedüs, Zita and Regenbach, Fruzsina L. and Keglevich, Péter and Lengyel, Zsófia and Gorka-Kereskényi, Álmos and Dubrovay, Zsófia and Háda, Viktor and Szigetvári, Áron and Szántay, Csaba (Ifj.) and Hazai, László and Tóvári, József and Hudecz, Ferenc (2018) The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell-penetrating peptide. JOURNAL OF PEPTIDE SCIENCE, 24 (10). e3118. ISSN 1075-2617

Bánóczi_Vindolin-oktaarginin_final_rev.pdf - Accepted Version

Download (445kB) | Preview


Some Vinca alkaloids (e.g. vinblastine, vincristine) have been widely used as antitumor drugs for a long time. Unfortunately, vindoline, a main alkaloid component of Catharanthus roseus (L.) G. Don, itself, has no antitumor activity. In our novel research program we have prepared and identified new vindoline derivatives with moderate cytostatic activity. Here we describe the effect of conjugation of vindoline derivative with oligoarginine (tetra-, hexa- or octapeptides) cell-penetrating peptides on the cytostatic activity in vitro and in vivo. Br-Vindoline-(L)-Trp-OH attached to the N-terminus of octaarginine was the most effective compound in vitro on HL-60 cell line. Analysis of the in vitro activity of two isomer conjugates (Br-vindoline-(L)-Trp-Arg8 and Br-vindoline-(D)-Trp-Arg8 suggest the covalent attachment of the vindoline derivatives to octaarginine increased the antitumor activity significantly against P388 and C26 tumour cells in vitro. The cytostatic effect was dependent on the presence and configuration of Trp in the conjugate as well as on the cell line studied. The configuration of Trp notably influenced of the activity on C26 and P388 cells: conjugate with (L)-Trp was more active than conjugate with the (D)-isomer. In contrast conjugates had very similar effect on both the HL-60 and MDA-MB-231 cells. In preliminary experiments conjugate Br-vindoline-(L)-Trp-Arg8 exhibited some inhibitory effect on the tumor growth in P388 mouse leukemia tumor-bearing mice. Our results indicate that the conjugation of modified vindoline could result in an effective compound even with in vivo antitumor activity.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: Dr Katalin Uray
Date Deposited: 30 Jan 2019 08:19
Last Modified: 06 Aug 2019 23:15

Actions (login required)

Edit Item Edit Item