PhD Scientific Days 2022

Pharmaceutical Sciences III. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Analysis of gene expression underlying the antitumor activity of TIC-10 and its fluorinated derivatives in a gemcitabine-resistant pancreatic adenocarcinoma cell line

Előadó neve

Szász, Zsófia

Előadó munkahelye

Semmelweis University, Department of Genetics, Cell- and Immunobiology

Előadó telefonszáma

+36709475934

Előadó e-mail címe

szaszadriennzsofia@gmail.com

Az előadás címe

Analysis of gene expression underlying the antitumor activity of TIC-10 and its fluorinated derivatives in a gemcitabine-resistant pancreatic adenocarcinoma cell line

Szerző(k) neve és munkahelye

Zsófia Szász, Semmelweis University, Department of Genetics, Cell- and Immunobiology, Budapest

Bemutatás módja

Poszter

Szekció

Pharmaceutical Sciences III. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Language of the presentation

Hungarian

Preferred session

Pharmaceutical Sciences

Összefoglaló szövege

INTRODUCTION: Pancreatic adenocarcinoma (PDAC) is one of the most lethal cancer types. It is often resistant to gemcitabine, a commonly used agent in its therapy. Today, several targeted therapeutic agents are in clinical trials for the treatment of PDAC, among them TRAIL-inducing compound 10 (TIC-10) shows great promise.
AIM: The main objective of the present work is to investigate (i) the antitumor effect of TIC-10 and its two fluorinated derivatives (TBP-134, TBP-135) on gemcitabine-resistant PDAC cells (PANC-1) and (ii) the gene expression changes underlying their action.
METHODS: For the viability and IC50 determinations, impedimetry (xCELLigence SP) and AlamarBlue assay were used. The gene expression studies were conducted by RT-qPCR and protein arrays.
RESULTS: The IC50 for gemcitabine was >50 μM after 96 h, thus PANC-1 cells were proved to be resistant to this drug. The IC50 of TBP-134 and TBP-135 molecules could be determined already after 72h (0.35 and 1.8 μM), whereas for TIC-10, we could detect IC50 value (1.8 μM) only after 96h. Changes in gene expression were examined at the protein level by measuring changes in both pro- and anti-apoptotic proteins. All three molecules increased the levels of pro-apoptotic proteins, including death receptors (DR4, DR5), various activated forms of p53 protein and cleaved caspase-3. The levels of anti-apoptotic proteins were increased by TIC-10, but decreased by TBP-134 and TBP-135. The apoptotic effect of the TRAIL inducing compounds was monitored by analysis of changes in the mRNA expression of TRAIL, DR4, DR5 and p53 genes. TBP-135 was able to increase TRAIL expression by 2.34-fold after 3h of treatment. All three compounds could increase the expression of DR4 and DR5, which effect proved to be time-dependent in the case of TIC-10 and TBP-134. The treatment with 25 μM TBP-134 increased p53 expression by 3.7-fold.
CONCLUSION: Our results suggest that TIC-10 and its derivatives are able to selectively induce apoptosis in the gemcitabine-resistant PANC-1 cell line. A difference in mechanism of action was observed: TBP-135 induced simultaneous activation of the extrinsic and intrinsic apoptotic pathways, similar to TIC-10, while TBP-134 induced only the activation of the intrinsic pathway.
FUNDING: EFOP-3.6.3-VEKOP-16-2017-00009

University and Doctoral School

Semmelweis University, Doctoral School of Pharmaceutical Sciences

Supervisor

Dr. med.habil. Kőhidai László

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6041

Start

12:55

End

13:00

Authors (legacy)

Zsófia Szász, Semmelweis University, Department of Genetics, Cell- and Immunobiology, Budapest