Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile

Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three...

Full description

Saved in:
Bibliographic Details
Published in:Pharmaceuticals (Basel, Switzerland) Vol. 17; no. 3; p. 389
Main Authors: Pillpe-Meza, Raysa Magali, Gouveia, Wesley Leandro, Barbosa, Gisele, Fraga, Carlos A M, Barreiro, Eliezer J, Lima, Lidia Moreira
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01-03-2024
MDPI
Subjects:
Analysis
antiproliferative activity
cancer
Cell cycle
Cell-mediated cytotoxicity
Cytotoxicity
Design
Drug metabolism
Epigenetics
HDAC-6
Health aspects
Histones
Kinases
Leukemia
Metabolism
Mutation
Pharmacokinetics
PI3K
Prostate
synergism
Brazil
DMPK
PI3K
synergism
cancer
HDAC-6
antiproliferative activity
cytotoxicity
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC = 23 µM), human leukaemia cell line CCRF-CEM (IC = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC = 5.44 µM), low absorption by parallel artificial membrane permeability-gastrointestinal tract (PAMPA-GIT) and low permeation by parallel artificial membrane permeability-blood-brain barrier (BBB) (PAMPA-BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC values on MOLT-4 and CCRF-CEM cells.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1424-8247
1424-8247
DOI:10.3390/ph17030389