Targeting on Poly (ADP-ribose) polymerase activity with DNA damaging hybrid lactam-steroid alkylators in wild type and BRCA1 mutated ovarian cancer cells.

Targeting on Poly (ADP-ribose) polymerase activity with DNA damaging hybrid lactam-steroid alkylators in wild type and BRCA1 mutated ovarian cancer cells.

Chem Biol Drug Des. 2017 Apr 22;:

Authors: Trafalis DT, Polonifi A, Dalezis P, Nikoleousakos N, Katsamakas S, Sarli V

Abstract
Conjugated lactam-steroid alkylators (LSA), have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemotherapy. Hybrid LSAs combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSAs that generate excellent anticancer activity against UWB1.289 and UWB1.289+BRCA1 human ovarian cancer cell lines. Both UWB1.289 and UWB1.289+BRCA1 cells carry mutations in the tumor suppressor gene TP53 while UWB1.289 cell line carries a germline BRCA1 mutation. In vitro, in vivo and in silico experimental methods were utilized to determine the Poly (ADP-ribose) polymerases (PARPs) activity and mRNA transcription, DNA damage, cytostatic and cytotoxic effects and virtual molecular interactions, in order to study the molecular mechanisms of activity of the tested LSAs. LSAs produce anticancer activity through dual action by combining the direct induction of cellular DNA damage with the inhibition of PARP activity and consecutive DNA repair activity. BRCA1 mutated UWB1.289 ovarian cancer cells with defective PARP-oriented repair mechanism show significantly higher sensitivity to these agents. Combined drug effect on DNA damage and repair is a novel approach in cancer therapeutics. This article is protected by copyright. All rights reserved.

PMID: 28432813 [PubMed - as supplied by publisher]

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