PO-059 IBTK promotes B cell lymphomagenesis in Eμ-MYC transgenic mice conferring resistance to apoptosis

Abstract

IntroductionAlbeit the advancement in breast cancer (BC) treatment, BC remains as the second leading cause of cancer death worldwide. Unlike the other BC subtypes, the lack of hormone receptor (HR) rendering the aggressive triple negative BC (TNBC) towards chemotherapy which is destructive to one’s quality of life. Tumour necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent due to its selective killing of malignant cells leaving the normal cells unharmed. Despite being TRAIL-sensitive, the TNBC MDA-MB-231 cells develop resistance to TRAIL after repeated treatment. The epigenetic drugs zebularine (Zeb) and trichostatin A (TSA) were reported to increase the TRAIL-induced apoptosis. Therefore, we aim to study the combinational anti-cancer effect of Zeb and TSA followed by TRAIL (TZT treatment) and compare its effect with the standard chemotherapy drug doxorubicin (DOX).Material and methodsMDA-MB-231, MCF-7 (HR positive breast cancer cells) and MCF-10A (normal breast epithelial cells) were treated with TZT and DOX respectively and subjected to cell proliferation, cell cycle arrest and apoptosis analyses.Results and discussionsBased on the results obtained, TZT treatment hampered the cell proliferation in MDA-MB-231 and MCF-7 as compared to TRAIL treatment alone but not in MCF-10A. Nevertheless, the cell proliferation of both breast cancer and normal cells treated with DOX was significant reduced. Subsequently, the cell cycle distribution was evaluated via flow cytometry analysis. Higher induction of G1 cell cycle arrest was observed in the MDA-MB-231 treated with TZT (57.5%) as compared to TRAIL alone (52.2%) at 24 hours. In MCF-7, there is the minimal induction of G1 arrest with TZT treatment (71.2%) as compared to TRAIL alone (69.7%) at 24 hours. However, DOX treatment induced G2/M arrest in breast cancer and normal cells. Furthermore, the morphological features of apoptosis were determined by haematoxylin and eosin staining. Intriguingly, the hallmark of apoptosis was clearly observed in breast cancer treated with TZT compared to MCF-10A. The results suggest the significance of Zeb and TSA to foster the TRAIL-induced apoptosis in TNBC but not in normal breast epithelial cells, despite further molecular analyses are requisite to validate the enhancement of apoptosis induction.ConclusionThis research provides an insight of potential alternative of TZT in treating the TNBC to improve the patients’ prognosis in the near future.