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
3690 - PD-L1 expression in resected undifferentiated pleomorphic sarcoma and its clinical implications
Presenter: Kyoungmin Lee
Session: Poster Display session 1
Resources:
Abstract
2013 - PD-L1 expression as a potential therapeutic target and prognostic biomarker in well-differentiated and dedifferentiated liposarcoma.
Presenter: Heejung Chae
Session: Poster Display session 1
Resources:
Abstract
5021 - Soft tissue sarcomas express a distinct mRNA immune profile
Presenter: Viktor Grünwald
Session: Poster Display session 1
Resources:
Abstract
3029 - The molecular landscape of fusion genes in endometrial stromal sarcomas include three nosological entities with different natural history
Presenter: Mehdi Brahmi
Session: Poster Display session 1
Resources:
Abstract
3914 - Clinical validation of a novel assay for the detection of diagnostic alterations in sarcomas
Presenter: Lauren Mc Connell
Session: Poster Display session 1
Resources:
Abstract
1912 - A prospective correlative trial of personalized patient-derived xenograft (PDX) as avatars for drug therapy in patients with metastatic or recurrent soft tissue sarcomas (STS).
Presenter: Kanan Alshammari
Session: Poster Display session 1
Resources:
Abstract
5097 - Fusion of immortalized myoblasts induces genomic instability that drives tumor development and progression.
Presenter: Candice Merle
Session: Poster Display session 1
Resources:
Abstract
1383 - let-7a suppress Ewing sarcoma CSCs' malignant phenotype through forms a positive feedback regulation loop with lin28 via STAT3
Presenter: Xu Jiang
Session: Poster Display session 1
Resources:
Abstract
3386 - Myoepithelial Tumors of Soft Tissues and Extraskeletal Myxoid Chondrosarcomas feature a distinct transcriptional pattern
Presenter: Dominga Racanelli
Session: Poster Display session 1
Resources:
Abstract
1844 - In Vivo Efficacy and Enhanced Tumor Accumulation of Liposomal Vinorelbine (TLC178) in Human Sarcoma Xenograft Mice Model
Presenter: Wan-ni Yu
Session: Poster Display session 1
Resources:
Abstract