A novel diquinolonium displays preclinical anti-cancer activity and induces caspase-independent cell death.
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.
Hurren
Rose
R
Ontario Cancer Institute, Princess Margaret Hospital, 610 University Ave, Toronto, ON, Canada M5G 2M9.
Beheshti Zavareh
Reza
R
Dalili
Shadi
S
Wood
Tabitha
T
Rose
David
D
Chang
Hong
H
Jamal
Nazir
N
Messner
Hans
H
Batey
Robert A
RA
Schimmer
Aaron D
AD
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D007928:Lethal Dose 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D051379:Mice; D008811:Mice, Inbred DBA; D011806:Quinolinium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D020298:U937 Cells
C529855:1-methyl-2-(3-(1-methyl-1,2-dihydroquinolin-2-yliden)prop-1-enyl)quinolinium iodide; D000590:Amino Acid Chloromethyl Ketones; D011806:Quinolinium Compounds; C460579:benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D020169:Caspases