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

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.

• Authors: Sonia How Ming Wong, Chee-Mun Fang, Hwei-San Loh, Siew Ching Ngai
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 23 Issue 7 Pg. 817-831 ( 2023) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 36380402 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• Catalase
• Ligands
• pyrimidin-2-one beta-ribofuranoside
• trichostatin A
• Proteome
• Tumor Necrosis Factor-alpha
• Inhibitor of Apoptosis Proteins
• Proto-Oncogene Proteins c-bcl-2
• Cadherins
• TNF-Related Apoptosis-Inducing Ligand

Topics

• Humans
• Female
• Catalase
• Ligands
• Proteome (pharmacology)
• Cell Line, Tumor
• Apoptosis
• Breast Neoplasms (pathology)
• Tumor Necrosis Factor-alpha
• Inhibitor of Apoptosis Proteins
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Cadherins
• Adenocarcinoma
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)