2026-09-24T17:58:01Zhttps://iris.unica.it/oai/requestoai:iris.unica.it:11584/2667872022-10-20T09:33:21Zcom_11584_207615com_11584_111066col_11584_265854
Biochemical, computer, and spectroscopic techniques applied to the study of prions and of combinations of antineoplastic drugs
PERRA, DANIELA
Artificial Neural Network
PrPSc
anticancer agents
prion structure
Settore BIO/19 - Microbiologia Generale
This thesis collects the work I have done during the three-year PhD Course. The results obtained
are divided according to the research topics addressed:
· Drug discovery of anticancer agents and development of synergistic associations (Part I);
· Studies on the prion structure and the pathogenesis of prion diseases (Part II).
Studies referring to the Part I have been carried out at the University of Cagliari and were focalized
on the evaluation and experimental validation of the method known as Artificial Neural Network
(ANN), which allows to determine, and also to predict, types and degree of interaction of two or
more drugs in combination with one another(s). I have successfully applied the ANN approach to
combinations of two cytotoxic compounds, i.e. cis-platinum (CDDP), a potent antineoplastic used
in the therapy of some types of carcinoma, with Cu(II) complexes that were previously shown to
be endowed with potent cytotoxic activity in vitro (Pivetta et al., J Inorg Biochem. 2011 and 2012).
Binary combinations comprising CDDP and Cu(II) complexes revealed (Part I, Chapter I) a strong
synergistic cytotoxic effect against leukemia cell lines (Pivetta et al., Talanta 2013). The synergistic
effect was confirmed in CDDP-resistant leukemia and ovarian cancer cell lines (Part I, Chapter II).
Investigations on molecular bases of the CDDP – Cu(II) complexes synergism are in progress.
As for the Part II of my research, I firstly investigated the mechanisms underlying the process of
generation of pathogenic prion protein (PrPSc). These studies were carried out in part at the
University of Cagliari, and in part at the Rocky Mountains Laboratories (RML) of the NIAID/NIH in
USA (Hamilton, Montana), during my 14-month research internship as supplemental visiting fellow
in a graduate partnership program. The studies carried out in Cagliari have investigated 1H NMR
modifications of brain metabolite profiles in sheep from a Sardinian farm hit by natural Scrapie
with the aim to discriminate infected vs. Uninfected, and early vs. late phases of the prion
infection (Part II, Chapter I). The overall results, obtained by different chemometric tools, were
able to describe a metabolite profile of scrapie-infected sheep brain, with and without clinical sign,
different to that of healthy ones, and to suggest Ala as a biomarker of PrPSc deposition (Scano et
al., J Molecular Biosystem, 2015)
Studies conducted at the RML of NIAID/NIH have addressed the structural features of PrPSc in
order to identify regions of the protein involved in the process of misfolding (Part II, Chapter II). So
far, data suggest that i) the N-terminal portion of the prion protein may have a role in the
modulation of the protein aggregation process, typical of prion diseases, while ii) the central
portion seems capable to undergo aggregation into fibrils even in the absence of other regions of
the protein. However, further studies are needed to confirm the proposed role in
promoting/hindering the misfolding and subsequent aggregation process of the various protein
regions.
2015-05-22
info:eu-repo/semantics/doctoralThesis
http://hdl.handle.net/11584/266787
eng
numberofpages:108
info:eu-repo/semantics/openAccess
Università degli Studi di Cagliari
license:Non specificato