Abstract 2644
Background
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Despite considerable research and advancement in CRC diagnosis and therapy, CRC is still clinically challenging and becoming the highest incidence cancer worldwide. There is a need to develop novel therapeutic agents for this malignancy.
Methods
MHY446, a novel histone deacetylase inhibitor (HDACi), was synthesized on the backbone of hydroxamic acid derivatives that are one of the HDAC inhibitors. We evaluated cytotoxic effects and underlying molecular mechanisms of actions of MHY446 in HCT116 human colorectal cancer cells.
Results
MHY446-treated HCT116 cells exhibited cell viability inhibition and an increase in the sub-G1 phase populations and late apoptosis. MHY446-induced apoptosis is accompanied by the activation of caspase-8, -9, and -3; subsequent cleavage of poly(ADP-ribose) polymerase; and alteration in the ratio of Bax/Bcl-2 protein expression level. The presence of Z-VAD-FMK, a pan-caspase inhibitor, significantly attenuated the MHY446-induced apoptosis indicating that apoptotic cell death was caspase-dependent cascading through the activation of both intrinsic and extrinsic signaling pathways. Furthermore, MHY446 caused the loss of mitochondria membrane potential and induced the generation of reactive oxygen species (ROS), evidenced by the scavenging of ROS by N-acetyl-L-cysteine (NAC). Additionally, MHY446 promoted the upregulation of the expression level of endoplasmic reticulum (ER) stress-associated proteins such as BIP, PDI, IRE1α, PERK, p-elF2α, and CHOP. NAC effectively reduced the expression of ER stress-related protein levels, suggesting that ROS acts as an upstream signaling molecule in triggering the ER stress pathway.
Conclusions
Taken together, these results demonstrate that MHY446 exerts its anticancer activities through the regulation of ROS-induced ER stress. These results suggest that MHY446 is a promising candidate for the treatment of CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5595 - Is there any prognostic significance in pleural involvement and/or effusion (Ple-I/E) in patients with ALK-positive NSCLC?
Presenter: Saadettin Kilickap
Session: Poster Display session 1
Resources:
Abstract
5840 - Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase 2 clinical trial – Updated progression-free survival, overall survival and mechanisms of resistance
Presenter: Sebastian Michels
Session: Poster Display session 1
Resources:
Abstract
1905 - NTRK1-3 Genomic Fusions in Non-Small Cell Lung Cancer (NSCLC) Determined by Comprehensive Genomic Profiling
Presenter: Sai-Hong Ou
Session: Poster Display session 1
Resources:
Abstract
3016 - Preferential expression of the affected MET allele in lung carcinomas with heterozygous MET exon 14 skipping mutations: implications for clinical testing
Presenter: Evgeny Imyanitov
Session: Poster Display session 1
Resources:
Abstract
4120 - Brain metastases, treatment patterns and outcomes in ROS1-positive NSCLC patients from US oncology community centers
Presenter: Matthew G Krebs
Session: Poster Display session 1
Resources:
Abstract
3764 - Patients with metastatic non-small cell lung cancer and targetable molecular alterations in Germany. Treatment and first outcome data from the prospective German Registry Platform CRISP (AIO-TRK-0315)
Presenter: Frank Griesinger
Session: Poster Display session 1
Resources:
Abstract
4070 - Crizotinib vs Platinum-based Chemotherapy as First-line Treatment for Advanced Non-small Cell Lung Cancer with Different ROS1 Fusion Variants
Presenter: Haiyan Xu
Session: Poster Display session 1
Resources:
Abstract
5528 - Genomic and clinical characterization of Non-small cell lung cancer (NSCLC) patients harboring mutations in FGFR2 and FGFR3
Presenter: Matthias Scheffler
Session: Poster Display session 1
Resources:
Abstract
3779 - The expression of HER2-gene polymorphisms -1985G>T and P1170A C>G and their association with the risk of development of lung adenocarcinoma
Presenter: Ivan Aleric
Session: Poster Display session 1
Resources:
Abstract
3020 - Circulating tumor DNA (ctDNA) analysis depicts mechanisms of resistance and tumor response to BRAF inhibitors in BRAF-mutant non-small cell lung cancer (NSCLC)
Presenter: Sandra Ortiz - Cuaran
Session: Poster Display session 1
Resources:
Abstract