Role of endogenous hydrogen sulfide in cancer cell proliferation

Postgraduate Thesis uoadl:1689936 657 Read counter

Unit:
Κατεύθυνση Σχεδιασμός και Ανάπτυξη νέων Φαρμακευτικών Ενώσεων - Φαρμακολογία
Library of the School of Science
Deposit date:
2017-06-28
Year:
2017
Author:
Damopoulou Georgia
Supervisors info:
Παπαπετρόπουλος Ανδρέας, Kαθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
Ο ρόλος του ενδογενώς παραγόμενου υδροθείου στον πολλαπλασιασμό καρκινικών κυττάρων
Languages:
Greek
Translated title:
Role of endogenous hydrogen sulfide in cancer cell proliferation
Summary:
Over the last decades, thorough research has been carried out in the field of
gasotransmitters. In addition to nitric oxide (NO) and carbon monoxide (CO), another
focal point has been hydrogen sulfide (H2S), the third gasotransmitter. In mammals,
H2S is endogenously produced by three enzymes: cystathionine β-synthase (CBS),
cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) or by
non-enzymatic pathways. The biological role and signaling pathways in which H2S is
involved have been the subject of various studies, both at a physiological and a
pathophysiological level. Recent research has focused on the underlying mechanisms
that correlate hydrogen sulfide to the biology of cancer.
In this context, hydrogen sulfide presents a bipolar character, as it can display
anticancer effects not only by the inhibition of its intrinsic biosynthesis but also by the
elevation of its levels beyond a certain point. Multiple mechanisms contribute to these
effects, including signaling pathways that involve suppression of mitochondrial
function, inhibition of angiogenesis, cell cycle arrest and induction of apoptosis.
Pharmacological tools, such as inhibitors of H2S biosynthesis as well as H2S donors,
are used to investigate the role of the gaseous transmitter in various types of cancer
together with its effect on the tumour proliferation, metabolism and growth in both in
vitro and in vivo experiments.
The aim of the present study is to elucidate the role of endogenous H2S regarding in
vitro models of ovarian cancer (TOV-21G and ES-2) and prostate cancer (PC-3 and
LNCaP). In the first place, we tested whether CBS, CSE and 3-MST are expressed in
the cancer cell lines at subject or not. After verifying their expression, we established
the optimal conditions (number of cells, MTT incubation time) for performing the MTT
colorimetric assay to determine cell proliferation afterwards. Ιnhibitors of the three
enzymes were then administered to the cancer cells at various concentrations for 48
hours and their effect on cell proliferation was investigated by the aforementioned
method. In all cancer cell lines, the most potent was CBS/CSE inhibitor, AOAA,
considering that its ability to reduce cell proliferation rate was the greatest among the
three. However, between the two types of cancer, AOAA had greater efficacy against
ovarian cancer (IC50 estimated at 684,7uM and 906,3uM for TOV-21G and ES-2
respectively) rather than prostate cancer (ΙC50>>1mM). Taking into account the
complex pharmacological profile of AOAA, we further determined whether AOAA
anticancer effects were due to the inhibition of H2S biosynthesis. Indeed, by
administrating simultaneously a hydrogen sulfide donor, GYY4137, the observed
inhibition over cell proliferation caused by AOAA was significantly reversed. In conclusion, future efforts should focus on the inhibition of endogenously produced H2S
as a new therapeutic approach as regards ovarian cancer.
Main subject category:
Science
Other subject categories:
Pharmacy
Pharmacology
Keywords:
hydrogen sulfide, pharmacological inhibitors, cancer, cell proliferation
Index:
Yes
Number of index pages:
94
Contains images:
Yes
Number of references:
171
Number of pages:
99
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