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
5638 - Incidence of Vascular Thromboembolism Events in Cancer Patients Receiving Immunotherapy: A Single Institution Experience.
Presenter: Laura Gutiérrez Sainz
Session: Poster Display session 1
Resources:
Abstract
5182 - High Incidence of Venous Thromboembolic Events (VTE) in Patients with Diffuse Large B-Cell Lymphoma.
Presenter: Alaa Abufara
Session: Poster Display session 1
Resources:
Abstract
1504 - Weight Loss over Time in Non-Small Cell Lung Cancer: Results from a Landmark Analysis of 800+ Prospectively-Treated Patients
Presenter: Jennifer Le-rademacher
Session: Poster Display session 1
Resources:
Abstract
3972 - The prognostic significance of preoperative nutritional status in resected pancreatic ductal adenocarcinoma (PDAC).
Presenter: Salvatore Paiella
Session: Poster Display session 1
Resources:
Abstract
2313 - Impact of Timing and Technique of Gastrostomy Placement on the Outcome of Patients (pts) with Head and Neck Cancer (HNC)
Presenter: M Julia Lostes Bardaji
Session: Poster Display session 1
Resources:
Abstract
5219 - Clinical & nutritional determinants of quality of life in patients with incurable cancer
Presenter: Louise Daly
Session: Poster Display session 1
Resources:
Abstract
4075 - Loss of skeletal muscle mass during palliative chemotherapy is a poor prognostic factor in patients with advanced gastric cancer
Presenter: In Gyu Hwang
Session: Poster Display session 1
Resources:
Abstract
4159 - Impact of nutritional derangement on treatment outcome in advanced non-small-cell lung cancer (A-NSCLC) patients (pts).
Presenter: Ilaria Trestini
Session: Poster Display session 1
Resources:
Abstract
1210 - Sarcopenia and pretreatment anemia as prognostic factors for patients with localized muscle invasive bladder cancer treated by neoadjuvant chemotherapy and radical cystectomy
Presenter: Emilien Billon
Session: Poster Display session 1
Resources:
Abstract
2490 - Gender effect on the pharmacokinetics (PK) and pharmacodynamics (PD) of anamorelin (ANAM) in healthy volunteers and cancer patients with cachexia
Presenter: Stein Kaasa
Session: Poster Display session 1
Resources:
Abstract