TY - JOUR
TI - Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced
by B-Lactam Steroid Alkylators with Targeted Activity against Poly
(ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay
AU - Nikoleousakos, Nikolaos
AU - Dalezis, Panagiotis
AU - Polonifi, Aikaterini
AU - and Geromichalou, Elena G.
AU - Sagredou, Sofia
AU - Alifieris,
AU - Constantinos E.
AU - Deligiorgi, V, Maria
AU - Sarli, Vasiliki and
AU - Trafalis, Dimitrios T.
JO - BioMedicine
PY - 2021
VL - 9
TODO - 8
SP - null
PB - MDPI
SN - 2211-8039
TODO - 10.3390/biomedicines9081028
TODO - anticancer drug; B-lactam steroid alkylators; synthetic lethality; poly
(ADP-ribose) polymerase inhibitors; ovarian cancer; hybrid steroidal
alkylating agents
TODO - We evaluated three newly synthesized B-lactam hybrid homo-aza-steroidal
alkylators (ASA-A, ASA-B and ASA-C) for their PARP1/2 inhibition
activity and their DNA damaging effect against human ovarian carcinoma
cells. These agents are conjugated with an alkylating component (POPA),
which also served as a reference molecule (positive control), and were
tested against four human ovarian cell lines in vitro (UWB1.289 + BRCA1,
UWB1.289, SKOV-3 and OVCAR-3). The studied compounds were thereafter
compared to 3-AB, a known PARP inhibitor, as well as to Olaparib, a
standard third-generation PARP inhibitor, on a PARP assay investigating
their inhibitory potential. Finally, a PARP1 and PARP2 mRNA expression
analysis by qRT-PCR was produced in order to measure the absolute and
the relative gene expression (in mRNA transcripts) between treated and
untreated cells. All the investigated hybrid steroid alkylators and POPA
decreased in vitro cell growth differentially, according to the
sensitivity and different gene characteristics of each cell line, while
ASA-A and ASA-B presented the most significant anticancer activity. Both
these compounds induced PARP1/2 enzyme inhibition, DNA damage
(alkylation) and upregulation of PARP mRNA expression, for all tested
cell lines. However, ASA-C underperformed on average in the above tasks,
while the compound ASA-B induced synthetic lethality effects on the
ovarian cancer cells. Nevertheless, the overall outcome, leading to a
drug-like potential, provides strong evidence toward further evaluation.
ER -