PhD Scientific Days 2023

Pathology - Posters D

Tumor inhibitory mechanism of novel tamoxifen derivates on breast- and pancreatic cancer cell lines

Text of the abstract

Introduction: Tamoxifen is a well-known antitumor drug, that modulates several estrogen receptor (ER)-dependent and independent (i.e. off-target) cell physiological pathways. Based on previous research, conjugation of the original compound with ferrocene and halogen groups can significantly improve its cytotoxic effect.
Aims: The main objective of this study is to reveal the mechanism behind the improved antitumor effect of the ferrocene-linked (T5 and T15) and halogenated (T6) and tamoxifen derivates. To uncover the possible means of action (i) the ER expression profile of the model cells are screened, (ii) apoptosis induction and cell cycle arrest is measured, (iii) ROS production levels are quantified and (iv) ROS production regulatory pathways are described.
Methods: Three cell lines were used: PANC1 (pancreas adenocc.), MCF7 (ER+ breast adenocc.), MDA-MB231 (ER- breast adenocc.). The ER expression profile was described by indirect immunocytochemistry. Apoptosis induction and cell cycle arrest was quantified by flow cytometry. The ROS production was measured with ROS-Glo assay. ROS production regulatory pathways were assessed with RT-qPCR.
Results: MDA-MB231 and MCF7 cells express the ERβ isoform. On PANC1 cells neither of the derivates were able to induce apoptosis in the measured concentrate. On MDA-MB231 cells, the ferrocene-linked derivates significantly raised the number of apoptotic figures compared to tamoxifen. On MCF7 cells, the halogenated derivate was also able to induce apoptosis. Both the halogenated and ferrocene-linked derivates are able to increase the ROS production on our model cells. In MDA-MB231 cells, T15 elevated the levels of LDHA, GPX4, IL6 and PRDX3, while in PANC1, it increased the expression of NOS1, PRKBC, PRDX3, NOX1 and MPO.
Conclusion: The examined novel tamoxifen derivatives exert their tumor inhibitory effect in an ER- dependent and independent manner. One main course of off-target action is the observed apoptosis caused by the elevated ROS production, which is highly affected by the ER expression profile of the cell line.
Funding: This research was supported by the National Research, Development and Innovation Office (NVKP_16-1-2016-0036), by the Ministry of Innovation and Technology (ÚNKP-22-3-II-SE-77) and by the EFOP-3.6.3-VEKOP-16-2017-00009 project.