The Faculty of Chemistry invites to a WEBINAR by
dr JOANNA ZAWACKA-PANKAU
(visiting lecturer at University of Warsaw, Warsaw, Poland,
Karolinska Institute, Stockholm, Sweden)
Title: Drug repositioning to target p53 protein family
Date: June 5th (Friday) 2020 at 13:00
Online Venue: the Webinar link will be sent upon registration https://forms.gle/kao91EwA9JwcMyZ76
Detailed information is included in pdf invitation.
Drug repositioning strives at reusing existing drugs for new indications. It brings hope for the improved treatment of cancer patients by addressing the financial- and treatment-related toxicity of current cancer care.
The p53 and p73 belong to the p53 protein family and act as tumor suppressors. The Tp73 is expressed in two distinct isoforms: TA isoforms that function as tumor suppressors and ΔN isoforms recognized as oncogenes.
In drug repurposing approach, we showed that exo-protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid (ALA), a pro-drug applied to treat actinic keratosis, activates p53 and TAp73 and induces apoptosis in cancer cells. Next, PpIX inhibits p53/MDM2 and TAp73/MDM2 and TAp73/MDMX interactions. PpIX stabilizes TAp73 on protein level in cells and in vivo (1,2). An analog of PpIX, verteporfin (benzoporphyrin derivative), a compound used to treat age-related macular degeneration, activates p73 and inhibits thioredoxin reductase (TrxR), an oncogene and a key player in the defense of cancers against oxidative damage (3). The findings have significant clinical relevance in that they may accelerate the repurposing of verteporfin and ALA/PpIX in oncology for improved therapy of cancers which bear Tp53 gene mutations.
References:
1. Sznarkowska, A.; Kostecka, A; Kawiak, A.; Acedo, P.; Lion, M.; Inga, A.; Zawacka-Pankau, J. Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells. Cell Division (2018) 13: 10.
2. Jiang LM, N.; Acedo, P.; Zawacka-Pankau, J. Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukemia cells. Cell Death Discovery. 2019;77 (2019).
3. Acedo P, Fernandes, A., Zawacka-Pankau, J. Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy in TP53 mutant pancreatic tumors. Future Science OA, 2019, 5(2): FSO366. (2018).
