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Targeting on poly(ADP‐ribose) polymerase activity with DNA‐damaging hybrid lactam‐steroid alkylators in wild‐type and BRCA1‐mutated ovarian cancer cells
Author(s) -
Trafalis Dimitrios T.,
Polonifi Aikaterini,
Dalezis Panayiotis,
Nikoleousakos Nikolaos,
Katsamakas Sotirios,
Sarli Vasiliki
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13006
Subject(s) - dna repair , poly adp ribose polymerase , biology , ovarian cancer , dna damage , in silico , polymerase , dna , cancer cell , homologous recombination , cancer research , chemistry , gene , microbiology and biotechnology , cancer , biochemistry , genetics
Conjugated lactam‐steroid alkylators (LSA) have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemjournalapy. Hybrid LSA 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 LSA 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 LSA. LSA 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.