A novel class of piperidones exhibit potent, selective and pro-apoptotic anti-leukemia properties.
In the present pre-clinical study, a series of 1-[3-(2-methoxyethylthio)-propionyl]-3,5- bis(benzylidene)-4 piperidones and structurally-related compounds were observed to be cytotoxicin vitroto three human leukemia cell lines, namely Nalm-6, CEM and Jurkat. The 50% cytotoxic concentration (CC50) values of the three cell lines ranged between 0.9-126.4 µM and 0.3-11.7 µM at 24 and 48 h subsequent to exposure, respectively. The two lead compounds with sub-micromolar CC50concentrations, 1-(2-methoxyethylthio-propionyl)-3,5-bis(benzylidene)-4 piperidone (2a) and 3,5-bis(4-fluorobenzylidene)-1-[3-(2-methoxyethyl sulfinyl)-propionyl]-4-piperidone (3e), were selected for additional analyses. Several strategies were undertaken to determine whether the above piperidones caused cell death via apoptosis or necrosis on T-lymphocyte leukemia Jurkat cells. The results revealed that the two piperidones caused phosphatidylserine externalization, mitochondrial depolarization and activation of caspase-3, which are all biochemical hallmarks of apoptosis. In addition, the selected piperidones displayed selective cytotoxicity towards leukemia cells, and were less toxic in non-cancerous control cells. Therefore, the findings of the present study revealed that the novel piperidones 2a and 3e exert a selective cytotoxic effect on lymphocyte leukemia cells by favoring the activation of the intrinsic/mitochondrial apoptotic pathway.
Cytometry, Imaging and Screening Core Facility, Border Biomedical Research Center, Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968-0519, USA.
Larissa M
LM
Nunes
Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
Mohammad
M
Hossain
Cytometry, Imaging and Screening Core Facility, Border Biomedical Research Center, Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968-0519, USA.
Armando
A
Varela-Ramirez
Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
Umashankar
U
DAS
Cytometry, Imaging and Screening Core Facility, Border Biomedical Research Center, Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968-0519, USA.
Yoshira M
YM
Ayala-Marin
Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada.
Jonathan R
JR
Dimmock
Cytometry, Imaging and Screening Core Facility, Border Biomedical Research Center, Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968-0519, USA.
Renato J
RJ
Aguilera
apoptosis; leukemia; lymphoma; piperidone