Abstract
Quinolines are a class of chemical compounds with emerging anti-cancer properties. Here, we tested the activity of series of quinolines and quinoline-like molecules for anti-cancer activity and identified a novel diquinoline, 1-methyl-2-[3-(1-methyl-1,2-dihydroquinolin-2-yliden)prop-1-enyl]quinolinium iodide (Q(2)). Q(2 )induced cell death in leukemia, myeloma, and solid tumor cell lines with LD50s in the low to submicromolar range. Moreover, Q(2) induced cell death in primary acute myeloid leukemia (AML) cells preferentially over normal hematopoietic cells. In a mouse model of leukemia, Q(2) delayed tumor growth. Mechanistically, Q(2) induced cell death through caspase independent mechanisms. By electron microscopy, Q(2) increased cytoplasmic vacuolization and mitochondrial swelling. Potentially consistent with the induction of autophagic cell death, Q(2) treatment led to a punctate distribution of LC3 and increased MDC staining. Thus, Q(2) is a novel quinolinium with preclinical activity in malignancies such as leukemia and myeloma and warrants further investigation.
References
Aug 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·M J WeissL B Chen
Nov 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·T NunoshibaB Demple
Nov 4, 2000·The EMBO Journal·Y KabeyaT Yoshimori
Feb 21, 2002·Proceedings of the National Academy of Sciences of the United States of America·J F RiouJ L Mergny
Mar 23, 2002·Bioorganic & Medicinal Chemistry Letters·Patrizia AlbertiJean-Louis Mergny
Aug 2, 2002·Carcinogenesis·Peter MøllerSteffen Loft
Nov 24, 2004·Nature Cell Biology·Shigeomi ShimizuYoshihide Tsujimoto
Feb 3, 2005·Blood·Bing Z CarterAaron D Schimmer
May 17, 2005·Leukemia Research·Eva GaleanoPilar Sancho
Jun 27, 2006·Molecular Pharmacology·Smitha AntonyYves Pommier
Jul 5, 2006·Cancer Research·Ze-Hong MiaoYves Pommier
Jul 6, 2006·Apoptosis : an International Journal on Programmed Cell Death·Debbie M GurfinkelAaron D Schimmer
Jan 26, 2007·Leukemia Research·Pilar SanchoAna Isabel García-Pérez
May 17, 2007·Journal of the National Cancer Institute·Imtiaz A MawjiAaron D Schimmer
Aug 8, 2007·Biotechnology and Bioengineering·Sun Ok Hwang, Gyun Min Lee
Oct 6, 2007·Cell Death and Differentiation·Y ChenS B Gibson
Oct 19, 2007·Cancer Research·Kazunori SatoHiroyasu Esumi
Nov 6, 2007·Bioorganic & Medicinal Chemistry·Tomohiro ItohYukihiro Akao
Nov 23, 2007·Journal of Cell Science·Yongqiang ChenSpencer B Gibson
Jan 15, 2008·Cell·Beth Levine, Guido Kroemer
Citations
Jun 26, 2012·Chemical Research in Toxicology·Michael J TwinerGregory J Doucette
May 15, 2012·Haematologica·Lauren I Aronson, Faith E Davies
May 27, 2011·Critical Reviews in Oncology/hematology·Huseyin Atakan EkizYusuf Baran
Oct 15, 2013·Chemico-biological Interactions·C BincolettoS S Smaili
Aug 2, 2017·The Open Medicinal Chemistry Journal·Christian VélezBeatriz Zayas
Feb 13, 2014·PloS One·Ingeborg Y BartEsther de Vries
Sep 19, 2020·Current Topics in Medicinal Chemistry·Yanna MaoYongfang Yao