Abstract
Combined inhibition of EZH2 and histone deacetylases as a potential epigenetic therapy for human uterine sarcoma cells.
Author
person
Mervat Mostafa Omran
Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
info_outline
Mervat Mostafa Omran, Somayeh Vafaei, Ayman Al-Hendy, Qiwei Yang
Full text
Authors
person
Mervat Mostafa Omran
Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
info_outline
Mervat Mostafa Omran, Somayeh Vafaei, Ayman Al-Hendy, Qiwei Yang
Organizations
Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL
Abstract Disclosures
Research Funding
No funding received
None.
Background:
Uterine sarcoma is strongly associated with poor prognosis, high rates of recurrence, and metastasis. However, the molecular mechanisms underlying the origin and development of uterine sarcoma and treatment options are limited. Enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDACs) play an important role in cancer progression. This study aimed to assess the effect of targeting both EZH2 and HDACs on the phenotype of uterine sarcoma (US) cells.
Methods:
Tazemetostat (EPZ-6438, E7438), a potent, and selective EZH2 inhibitor, was first approved by the US Food and Drug Administration (FDA) in 2020. Entinostat (MS-275, SNDX-275) is one of the strong inhibitors for HDAC1 and HDAC3, Vorinostat is used to treat cutaneous T-cell lymphoma, Tucidinostat (Chidamide, HBI-8000, CS-055) is a low nanomolar inhibitor of HDAC1, 2, 3, and 10. Uterine sarcoma cell line (MES-SA) was treated with different concentrations (1.56-200 mM) of Tazemetostat and/or Entinostat, Vorinostat, Tucidinostat (Chidamide). for 24, 48, 72 h, respectively. Further mechanistic confirmation was carried out on best combination in both 2D and 3D culturing using IHC and real time PCR.
Results:
Our data showed that Entinostat synergistically (with a combination index 0.539) augments the cytotoxic activity of Tazemetostat in both 2D and spheroids
in vitro
model systems. The IC50 values for Tazemetostat were significantly reduced to 4.5 mM after combination treatment with 6.25 mM Entinostat for 48 h. Entinostat enhanced the antiproliferative effect of Tazemetostat with a decrease in the expression of proliferative markers Ki67(P < 0.0001) and PCNA (P < 0.01). Furthermore, combination treatment significantly increased US cell apoptosis, concomitantly with increased both BAX and Caspase-3 levels and decreased Bcl-2 (P < 0.0001) using 2D and spheroid in vitro model (P < 0.001). The finding was confirmed by IHC analysis in the US cell-derived spheroids.
Conclusions:
Our studies demonstrate that Entinostat, in combination with Tazemetostat proves significantly superior to either single treatment. Dual targeting EZH2 and HDACs may provide a promising treatment option for this aggressive cancer disease.
5 organizations
4 drugs
6 targets
Organization
Cancer Biology DepartmentOrganization
National Cancer Institute, Vilnius, LithuaniaOrganization
Cairo UniversityOrganization
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, ChinaOrganization
University of ChicagoDrug
tazemetostatDrug
entinostatDrug
vorinostatDrug
TucidinostatTarget
HDAC1Target
HDAC2Target
HDAC3Target
HDAC10Target
EZH2Target
HDACs