Selective Induction of Cellular Toxicity and Anti-tumor Efficacy by N-Methylpiperazinyl Diarylidenylpiperidone and its Pro-nitroxide Conjugate through ROS-mediated Mitochondrial Dysfunction and G2/M Cell-cycle Arrest in Human Pancreatic Cancer.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Cycle
/ drug effects
Cell Division
Cell Line, Tumor
Cell Survival
Drug Screening Assays, Antitumor
Electron Spin Resonance Spectroscopy
G2 Phase
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Mitochondria
/ drug effects
Neoplasm Transplantation
Oximetry
Pancreatic Neoplasms
/ drug therapy
Piperazines
/ pharmacology
Piperidones
/ pharmacology
Reactive Oxygen Species
/ metabolism
Diarylidenylpiperidone
Nitroxide
Pancreatic cancer
ROS
Tumor oxygen
Xenograft tumor
Journal
Cell biochemistry and biophysics
ISSN: 1559-0283
Titre abrégé: Cell Biochem Biophys
Pays: United States
ID NLM: 9701934
Informations de publication
Date de publication:
Jun 2020
Jun 2020
Historique:
received:
04
05
2020
accepted:
12
05
2020
pubmed:
26
5
2020
medline:
30
1
2021
entrez:
26
5
2020
Statut:
ppublish
Résumé
Pancreatic adenocarcinoma is an aggressive cancer with poor clinical prognosis and limited therapeutic options. There is a significant lack of effective, safe, and targeted therapies for successful treatment of pancreatic cancer. In this report, we describe the anticancer efficacy of two novel compounds, N-methylpiperazinyl diarylidenylpiperidone (L-2663) and its pro-nitroxide conjugate (HO-4589) evaluated on human pancreatic adenocarcinoma (AsPC-1) cell line and xenograft tumor in mice. Using flow cytometry, we determined the effect of the L-2663 and HO-4589 drugs in inducing mitochondrial toxicity, triggering cell-cycle arrest, and apoptosis. EPR spectroscopy was used to quantify cellular uptake, metabolic conversion and stability of HO-4589 in cells and in vivo monitoring of tumor oxygenation as a function of growth. The results established different antiproliferative efficacy of the L-2663 and HO-4589 compounds, with a targeted action on cancer cells while being less toxic to noncancerous cells. The study may have important implications in the future designs of safe and effective chemotherapeutic agents for the treatment of pancreatic cancer.
Identifiants
pubmed: 32449075
doi: 10.1007/s12013-020-00919-0
pii: 10.1007/s12013-020-00919-0
doi:
Substances chimiques
Antineoplastic Agents
0
Piperazines
0
Piperidones
0
Reactive Oxygen Species
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
191-202Subventions
Organisme : NIH HHS
ID : EB004031
Pays : United States
Organisme : NIH HHS
ID : EB004031
Pays : United States
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