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
5444 - Analysis of the tumor microenvironment and tumor genotype through different stages of lung adenocarcinoma
Presenter: Peter Zink
Session: Poster Display session 1
Resources:
Abstract
3124 - Does Progress achieved in the Treatment of Patients with Metastatic Non-Small-Cell Lung Cancer (NSCLC) reach the Elderly Population?
Presenter: Jorune Suipyte
Session: Poster Display session 1
Resources:
Abstract
5142 - Prognostic factors for non-small cell lung cancer patients with driver mutation negative and brain metastases (HOT 1701)
Presenter: Yoshihito Ohhara
Session: Poster Display session 1
Resources:
Abstract
1580 - A novel risk classification system based on nomogram scores to predict survival of patients presenting with brain metastases at the first diagnosis of NSCLC
Presenter: Pengfei Cui
Session: Poster Display session 1
Resources:
Abstract
4442 - Comparison of real-world response rate (rwRR) to RECIST-based response rate in patients with advanced non-small cell lung cancer (aNSCLC)
Presenter: Xinran Ma
Session: Poster Display session 1
Resources:
Abstract
5405 - Estimating the cost and survival impact of new aNSCLC therapies in Canada with the iTEN model
Presenter: Parneet Kaur Cheema
Session: Poster Display session 1
Resources:
Abstract
1893 - SMARCA4 Deficient Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Genomic Profiling (CGP) Study
Presenter: Stephen Graziano
Session: Poster Display session 1
Resources:
Abstract
5582 - Exploring Resistance to Nivolumab [NIV] applying an Immune Genomic Signature (IGS) in advanced pretreated NSCLC [PRINCiPe study]
Presenter: Sara Pilotto
Session: Poster Display session 1
Resources:
Abstract
1408 - DNA damage repair deficiency is associated with early resistance to crizotinib: whole-genome analysis in non-small cell lung cancer patients with ALK-fusion
Presenter: Dongyun He
Session: Poster Display session 1
Resources:
Abstract
5751 - Phase 3 ALTA-3 study of brigatinib (BRG) vs alectinib (ALC) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)−positive non–small cell lung cancer (NSCLC) that progressed on crizotinib (CRZ)
Presenter: Sanjay Popat
Session: Poster Display session 1
Resources:
Abstract