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The effect of conjugation on antitumor activity of vindoline derivatives with octaarginine, a cell‐penetrating peptide
Author(s) -
Bánóczi Zoltán,
Keglevich András,
Szabó Ildikó,
Ranđelović Ivan,
Hegedüs Zita,
Regenbach Fruzsina L.,
Keglevich Péter,
Lengyel Zsófia,
GorkaKereskényi Álmos,
Dubrovay Zsófia,
Háda Viktor,
Szigetvári Áron,
Szántay Csaba,
Hazai László,
Tóvári József,
Hudecz Ferenc
Publication year - 2018
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.3118
Subject(s) - vindoline , conjugate , vinblastine , catharanthus roseus , chemistry , in vitro , vinca alkaloid , vinca , cell culture , in vivo , biochemistry , stereochemistry , pharmacology , biology , vincristine , mathematical analysis , genetics , mathematics , microbiology and biotechnology , chemotherapy , cyclophosphamide
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‐Arg 8 and Br‐vindoline‐( d )‐Trp‐Arg 8 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‐Arg 8 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.