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

Zoltán Bánóczi, András Keglevich, Ildikó Szabó, Ivan Ranđelović, Zita Hegedüs, Fruzsina L. Regenbach, Péter Keglevich, Zsófia Lengyel, Álmos Gorka-Kereskényi, Zsófia Dubrovay, Viktor Háda, Áron Szigetvári, Csaba Szántay, László Hazai, József Tóvári, Ferenc Hudecz

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Abstract

Some Vinca alkaloids (eg, 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 suggests 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 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.

Original languageEnglish
Article numbere3118
JournalJournal of Peptide Science
Volume24
Issue number10
DOIs
Publication statusPublished - Oct 2018

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Keywords

  • Vinca alkaloids
  • antitumor activity
  • cell-penetrating peptide
  • peptide-conjugates
  • vindoline

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Bánóczi, Z., Keglevich, A., Szabó, I., Ranđelović, I., Hegedüs, Z., Regenbach, F. L., Keglevich, P., Lengyel, Z., Gorka-Kereskényi, Á., Dubrovay, Z., Háda, V., Szigetvári, Á., Szántay, C., Hazai, L., Tóvári, J., & Hudecz, F. (2018). The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell-penetrating peptide. Journal of Peptide Science, 24(10), [e3118]. https://doi.org/10.1002/psc.3118