Anti-STAT3 and -NF-kB phytocompounds against glioma

Data inizio
25 maggio 2010
Durata (mesi) 
Responsabili (o referenti locali)
Suzuki Hisanori

apoptosis. The capacity to avoid apoptotic suicide, often correlated to tumour aggressiveness and resistance to traditional chemiotherapeutic drugs, permits
transformed cells to diffuse and metastasize in the sites where usually it is very hard to survive. In this context, it is important to note that tumour cells may not be
immortal, rather less mortal than normal cells, due to the partial loss of their innate capacity to enter in auto-disruption in response to circumstantial signals.
These considerations have led to the increasing interest to understand the molecular mechanism involved in the regulation of cell death and survival and, thus, to find
new therapeutic targets. An increasing body of literature indicates that the activation of signal transducer and activator of transcription (STAT) family of nuclear
transcriptional factors such as STAT3 may be deeply involved in the development of a number of tumours due to the deregulation of their intracellular pathways and
successive acquirement of incapacity of cells to enter in apoptosis. Therefore, inhibition of some STATs is believed to represent a new approach to develop tumour
preventing and/or therapeutic drugs with a specific action and less harmful side effect.
Recently, we have identified two terpenes isolated from laurel leaves, custunolide and dehydrocostus lactone, with a strong anti-STAT3 activity. We also have
identified certain plant extracts with anti-STAT3 activity and we are going to identify the responsible compounds.
In the present project, we will study the effect of these compounds, together with those provided from the Salerno and Padova units, on the growth of a number of
transformed cells (primary blast cells from adult acute leukemia such as Acute myeloid leukemia (AML) and Chronic myeloid leukemia (CML), and human prostate
carcinoma cells) and TRAMP model of prostate carcinogenesis, a well known autochthonous transgenic animal model which is available in our unit. We will also
study the effect of phytocompounds on the growth of metastatic breast cancer cells obtained directly from the vertebrate biopsies of patients which will be provided by
the Rome unit. This study is aimed to correlate pro-apoptotic activity of some phytocompounds to their anti-STAT3/5 activity.
Since STAT3 are nuclear factors regulating the expression of genes intricately involved in neoplasia, analysis of gene/protein profiles before and after treatment with
anti-STAT3 pro-apoptotic phytocompounds will also be performed either by qRT-PCR methods or proteomics, this latter in a strict collaboration with Roman group.
This study will provide us with useful information on the identification of possible targets of the above-described phytocompounds.
In parallel we will study the molecular mechanism of anti-STAT3 action of these compounds by identifying their direct target molecules. For these studies we will use
SPR (Surface Plasmon Resonance) analysis to study the direct interaction between these compounds and proteins deeply involved in STAT3/5 pathways such as
cytokine-receptors, JAKs/Tyk or STAT3 proteins. Finally, computer modelling analysis will be performed to define the interaction site(s) and the nature of their
interaction. All these studies will provide a basis for the structure/function studies leading to the identification of new tumour preventing and/or therapeutic drugs.

Enti finanziatori:

Finanziamento: richiesto
Programma: PRIN