PhD Scientific Days 2024

Pharmaceutical Sciences and Health Technologies I.

ONC-201 and its Fluorinated Analogues: Characterization of Apoptotic Protein Expression of Gemcitabine-Resistant Pancreatic Cancer Cells

Előadó neve

Dr. Szász, Zsófia

Neptun code

IKMTJT

Előadó munkahelye

Department of Genetics, Cell- and Immunobiology

Előadó telefonszáma

+3612102930/56232

Előadó e-mail címe

szasz.adrienn@stud.semmelweis.hu

Az előadás címe

ONC-201 and its Fluorinated Analogues: Characterization of Apoptotic Protein Expression of Gemcitabine-Resistant Pancreatic Cancer Cells

Szerző(k) neve és munkahelye

Zsófia Szász¹, Angéla Takács¹, Petra Pőcze¹, Márton Kalabay¹, Péter Bárány², Tamás Czuczi², Antal Csámpai², Eszter Lajkó¹, László Kőhidai¹

1: Department of Genetics, Cell- and Immunobiology, Semmelweis University
2: Department of Organic Chemistry, Eötvös Loránd University

Bemutatás módja

Szóbeli

Szekció

Pharmaceutical Sciences and Health Technologies I.

Language of the presentation

English

Preferred session

Pharmaceutical Sciences and Health Technologies

Összefoglaló szövege

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate, the 5-year survival rate is ~12%. Resistance often develops during the treatment of gemcitabine monotherapy. For these reasons, the development of new targeted therapy is a matter of great urgency. One of the potential candidates is ONC-201, which is already being tested in clinical trials.
Aim: The main objective of the present work is to investigate the underlying molecular mechanism of the antitumour activity of ONC-201 and its two fluorinated analogues (TBP-134, TBP-135) and to determine their cardiotoxicity.
Methods: PANC-1 (PDAC cell line) – (i) protein expression study: Human Proteom Profiler Apoptosis Array kit and flow cytometer (Cytoflex), (ii) gene expression analysis: RT-qPCR (CFX96 Touch). HL-1 (mouse cardiomyocyte cell line) – characterisation of cardiotoxicity: CellTiter Glo.
Results: Four genes (DR4, DR5, p53, TRAIL) were analysed for RNA expression. TBP-134 significantly upregulated DR4 by 3.74-fold at 24 hours. DR5 was upregulated by ONC-201 and TBP-134 at 12 hours and by TBP-135 at 24 hours (5.90-fold). p53 expression increased aftter TBP-134 treatment (3.71-fold at 48 hours). TRAIL induction wasn't observed with ONC-201 or TBP-134, but TBP-135 showed a 2.36-fold increase. Treatment with the molecules at 0.5 μM for 72 hours induced changes in the expression profile of apoptotic proteins. ONC-201 increased pro-apoptotic proteins such as cleaved caspase-3, FADD, DR5, SMAC and phospho-p53, but also anti-apoptotic ones (e.g. XIAP). TBP-135 had the same effect as ONC-201, whereas a different protein profile was observed after treatment with TBP-134. Flow cytometry showed that ONC-201 and TBP-135 increased intracellular TRAIL levels similarly, while they influenced the cell surface level of the protein differently. In our cardiotoxicity study on HL-1 cells, no IC50 values could be calculated in the tested range (0.5-25 μM), in contrast to gemcitabine, which showed high cardiotoxicity (IC50 < 50 nM).
Conclusion: All three molecules exhibit a potent antitumour effect against PANC-1 cells without causing cardiotoxicity. They induce apoptosis primarily through the DR5 and DR4 pathways, with TBP-134 showing the highest efficacy. TBP-134 is a promising candidate for further studies to target pancreatic adenocarcinoma.
Funding: SE250+ fellowship, EFOP-3.6.3-VEKOP-16-2017-00009

University

Semmelweis University

Supervisor

László Kőhidai and Eszter Lajkó

Publication of my abstract

I give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6041

Start

17:00

End

17:10