| dc.description.abstract | During the course of my Ph.D., I focused my studies on two main topics: the cytotoxic effects induced
by 4-nonylphenol (4-NP) and 4-octylphenol (4-OP) and the anti-cancer properties of natural
cardenolides extracted from the aerial parts of the plant Pergularia tomentosa. For both topics, human
cell cultures were used as a suitable study model.
4-NP and 4-OP are widely distributed environmental pollutants in different compartments such as
water, soils and sediments. They are mainly derived from the degradation of polyethoxylated
alkylphenols, which due to their chemical characteristics are widely used in many industrial
applications. Humans are continuously exposed to these substances mainly through ingestion of
contaminated water and food, but also through inhalation and dermal absorption. After their
introduction into the human body, they accumulate in various organs and biological fluids,
particularly in the liver and intestine. They can act as endocrine disrupting chemicals and exert toxic
and harmful effects on many organs and tissues. Therefore, my aim was to understand the molecular
and biochemical mechanisms by which they induce cytotoxicity in human cell lines. The results of
my research revealed that alkylphenols (APs) profoundly alter human cell physiology by inducing
viability reduction linked to a cell cycle arrest and to the triggering of apoptosis. Moreover, they are
responsible for inducing organelles stress conditions and damage, such as ER-stress, altered calcium
homeostasis, mitochondrial dysfunction, oxidative stress and induction of autophagic flux.
The natural compounds, investigated in my research, have been extracted, from the first time, from
the leaves of P. tomentosa, a member of the Asclepiadaceae family. They belong to the group of
cardiac glycosides. Structurally, they have a steroid nucleus, a glycosidic portion and a lactone ring.
However, cardenolides extracted from P. tomentosa have peculiar structural features, i.e. transfused
A/B rings and sugar moiety linked by a double bond, generating the dioxanoid attachment. Precisely,
the compounds under investigation are calactin, calotropin and their derivatives. Over time, it has
been shown that cardiac glycosides, in addition to their classic cardiotonic action, are able to exert
effects that counteract cancer cells. Therefore, my aim, here, was to understand the molecular
mechanisms by which these compounds exerted their anti-cancer action. I realized, firstly, that the
compounds are not selective for tumour cells, however, calactin strongly reduces the viability of
HepG2 tumour cells on which, consequently, I decided to focus my attention. I showed that P.
tomentosa compounds reduced the viability, proliferation and migration of cancer cells. Furthermore,
they were able to trigger autophagy and apoptosis in the same cell line. In light of these results, they
represent good candidates for developing anti-cancer drugs or adjuvants to current therapies.
In conclusion, by using the same in vitro models represented by human cell cultures, and
similar methodological approaches, I obtained findings useful to elucidate the biochemical
and molecular mechanisms by which APs induced cytotoxicity and those underlying the
anti-tumour properties of P. tomentosa compounds. [edited by Author] | it_IT |
