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Trailing TRAIL Resistance in Human Breast Adenocarcinoma Cells with Trichostatin A and Zebularine

Sonia How Ming Wong¹, Chee-Mun Fang², Hwei-San Loh¹

¹School of Biosciences, Faculty of Science and Engineering, University of Nottingham Malaysia, 43500 Semenyih, Selangor, Malaysia.

Anti-Cancer Agents in Medicinal Chemistry

|November 16, 2022

Abstract

Aims:

The aim of this study was to sensitize the resistant breast adenocarcinoma cells towards Tumour Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced apoptosis.

Background:

Breast cancer is a heterogeneous disease involving complex mechanisms. TRAIL is a potential anticancer candidate for targeted treatment due to its selective killing effects on neoplastic cells. Nonetheless, resistance occurs in many cancers either intrinsically or after multiple treatments.

Objective:

Therefore, this research investigated whether the combination of Trichostatin A (TSA) and Zebularine (Zeb) (TZ) followed by TRAIL (TZT) could sensitize the human breast adenocarcinoma cells towards apoptosis.

Methods:

The breast adenocarcinoma cells, MDA-MB-231, MCF-7 and E-MDA-MB-231 (E-cadherin re-expressed MDA-MB-231) were treated with TSA, Zeb, TZ, TRAIL and TZT. The cells were subjected to hematoxylin and eosin (H & E) staining and FITC-Annexin V/Propidium Iodide apoptosis detection prior to proteome profiling.

Results:

Based on morphological observation, apoptosis was induced in all cells treated with all treatment regimens though it was more evident for the TZT-treated cells. In the apoptosis detection analysis, TZ increased early apoptosis significantly in MDA-MB-231 and MCF-7 while TRAIL induced late apoptosis significantly in E-MDA-MB-231. Based on the proteome profiling on MDA-MB-231, TRAIL R2 and Fas expression was increased. For E-MDA-MB- 231, down-regulation of catalase, paraoxonase-2 (PON2), clusterin, an inhibitor of apoptosis proteins (IAPs) and cell stress proteins validated the notion that E-cadherin re-expression enhances TZT anti-cancer efficacy. Similar trend was observed in MCF-7 whereby TZT treatment down-regulated the anti-apoptotic catalase and PON2, increased the proapoptotic, B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax), second mitochondria-derived activator of caspase (SMAC) and HtrA serine peptidase 2 (HTRA2) as well as TRAIL receptors (TRAIL R1 and TRAIL R2).

Conclusion:

TZ treatment serves as an efficient treatment regimen for MDA-MB-231 and MCF-7, while TRAIL serves as a better treatment option for E-MDA-MB-231. Therefore, future studies on E-cadherin's positive regulatory role in TRAIL-induced apoptosis are warranted.

Insights

This study combined Trichostatin A (TSA) and Zebularine (Zeb) with TRAIL to sensitize resistant breast cancer cells. The TZT combination enhanced apoptosis in various breast adenocarcinoma cell lines, offering new therapeutic strategies.

Area of Science:

Oncology
Molecular Biology
Cell Biology

Background:

Breast cancer is a complex disease with treatment resistance.
Tumor Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL) shows promise for targeted cancer therapy.
Acquired or intrinsic resistance limits TRAIL's efficacy in many cancers.

Purpose of the Study:

To investigate if combining Trichostatin A (TSA) and Zebularine (Zeb) with TRAIL (TZT) can sensitize resistant human breast adenocarcinoma cells to TRAIL-induced apoptosis.
To evaluate the efficacy of TZT treatment on different breast cancer cell lines, including those with re-expressed E-cadherin.

Main Methods:

Treatment of MDA-MB-231, MCF-7, and E-MDA-MB-231 cells with TSA, Zeb, TZ, TRAIL, and TZT.
Morphological assessment using Hematoxylin and Eosin (H&E) staining.
Apoptosis detection via FITC-Annexin V/Propidium Iodide staining.
Proteome profiling to analyze protein expression changes.

Main Results:

TZT treatment induced apoptosis in all tested cell lines, with enhanced effects observed in TZT-treated groups.
TZ significantly increased early apoptosis in MDA-MB-231 and MCF-7 cells.
E-cadherin re-expression in E-MDA-MB-231 cells enhanced TZT efficacy, indicated by down-regulation of anti-apoptotic proteins (catalase, PON2) and up-regulation of pro-apoptotic factors.
MCF-7 cells showed similar trends with TZT, including down-regulation of catalase and PON2, and up-regulation of Bad, Bax, SMAC, HTRA2, and TRAIL receptors.

Conclusions:

TZ is an effective regimen for MDA-MB-231 and MCF-7 cells, while TRAIL is more effective for E-cadherin-positive E-MDA-MB-231 cells.
E-cadherin plays a positive regulatory role in TRAIL-induced apoptosis, suggesting its potential as a biomarker or therapeutic target.
Further research into E-cadherin's role in TRAIL-mediated apoptosis is warranted for developing novel breast cancer treatments.

Read full analysis

Keywords:

TRAIL apoptosis breast cancer resistance trichostatin A zebularine

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