| Entinostat is an oral class I isoform-selective histone deacetylases (HDAC) inhibitor with IC50s of 0.51 and 1.7 µM for HDAC1 and HDAC3, respectively.[1] Entinostat inhibits cancer cell growth with a half maximal inhibitory concentration in the submicromolar range, and the inhibition is accompanied by cell cycle arrest and induction of the cyclin-dependent kinase (CDK) inhibitor p21waf1. Entinostat has shown promising activity against various cancer types, including colorectal, lung, ovarian, and pancreatic cancers, pediatric solid tumors, leukemia, prostate cancer, and breast cancer. Entinostat inhibits hodgkin lymphoma (HL) cell lines HD-LM2, L-428, KM-H2 with IC50s of 0.57, 0.39, 1.42 µM, respectively. [2] In addition, entinostat inhibits cell proliferation and inactivates downstream signaling in erbB2- overexpressing compared with basal breast cancer cells. Entinostat inhibits erbB2- overexpressing cells with IC50 ranging from 0.4 to 1.2 µM, and inhibits basal cells with IC50 ranging from 2.5 to 4.5 µM. Entinostat reduces the levels of both erbB2 and erbB3, as well as significantly decreases P-erbB2, P-erbB3, P-Akt, and P-MAPK in erbB2-overexpressing cells. [3] Meanwhile, treatment with entinostat increases acetylation of global H3 histones and the fas gene promoter in DLM8 cells. Entinostat can activate fas signaling by stimulating transcription of the fas gene and increasing the expression of fas mRNA and protein. [4] When administered at a low concentration of 1 µM, entinostat exhibits potent antiproliferative activity, inducing p21CIP1/WAF1-mediated growth arrest and expression of differentiation markers (CD11b) in U937 cells. At higher concentration of 5 µM, entinostat potently induces cell death, triggering apoptosis in 70% of cells at 48 hours. [5] In vivo, intranasal administration of entinostat for 5 weeks is well tolerated and significantly inhibits LM7 osteosarcoma (OS) metastasis growth in the lungs, indicating local administration of entinostat to the lungs by inhalation facilitates the delivery of a therapeutic dose. [4] In RENCA primary tumor model, MS-275 (5 mg/kg/day) administration induces a 40% reduction of tumor growth. The combination of MS-275 with IL-2 has a synergistic inhibitory effect compared with single agents alone (90% reduction). MS-275 treatment (5 mg/kg/day) also has an antimetastatic effect. The combination treatment with IL-2 has a greater effect as compared with MS-275 alone. The combination treatment MS-275 and IL-2 in the prevention tumor model results in a significant improvement in the survival of RENCA tumor-bearing animals as compared with either MS-275, IL-2, or control groups.[6] |
