Skip to main content

Advertisement

SpringerLink
Log in

A novel diquinolonium displays preclinical anti-cancer activity and induces caspase-independent cell death

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

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 (Q2). Q2 induced cell death in leukemia, myeloma, and solid tumor cell lines with LD50s in the low to submicromolar range. Moreover, Q2 induced cell death in primary acute myeloid leukemia (AML) cells preferentially over normal hematopoietic cells. In a mouse model of leukemia, Q2 delayed tumor growth. Mechanistically, Q2 induced cell death through caspase independent mechanisms. By electron microscopy, Q2 increased cytoplasmic vacuolization and mitochondrial swelling. Potentially consistent with the induction of autophagic cell death, Q2 treatment led to a punctate distribution of LC3 and increased MDC staining. Thus, Q2 is a novel quinolinium with preclinical activity in malignancies such as leukemia and myeloma and warrants further investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Rat P, Piard F, Gabrielle F, Haas O, Favre JP (1990) Gastric hemorrhage and thrombosis of the splenic artery. Gastroenterol Clin Biol 14(10):786–788

    PubMed  CAS  Google Scholar 

  2. Moller P, Wallin H, Vogel U, Autrup H, Risom L, Hald MT et al (2002) Mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in colon and liver of big blue rats: role of DNA adducts, strand breaks, DNA repair and oxidative stress. Carcinogenesis 23(8):1379–1385

    Article  PubMed  CAS  Google Scholar 

  3. Nunoshiba T, Demple B (1993) Potent intracellular oxidative stress exerted by the carcinogen 4-nitroquinoline-N-oxide. Cancer Res 53(14):3250–3252

    PubMed  CAS  Google Scholar 

  4. Weiss MJ, Wong JR, Ha CS, Bleday R, Salem RR, Steele GD Jr et al (1987) Dequalinium, a topical antimicrobial agent, displays anticarcinoma activity based on selective mitochondrial accumulation. Proc Natl Acad Sci USA 84(15):5444–5448

    Article  PubMed  CAS  Google Scholar 

  5. Sancho P, Galeano E, Nieto E, Delgado MD, Garcia-Perez AI (2007) Dequalinium induces cell death in human leukemia cells by early mitochondrial alterations which enhance ROS production. Leuk Res 31(7):969–978

    Article  PubMed  CAS  Google Scholar 

  6. Galeano E, Nieto E, Garcia-Perez AI, Delgado MD, Pinilla M, Sancho P (2005) Effects of the antitumoural dequalinium on NB4 and K562 human leukemia cell lines. Mitochondrial implication in cell death. Leuk Res 29(10):1201–1211

    Article  PubMed  CAS  Google Scholar 

  7. Alberti P, Schmitt P, Nguyen CH, Rivalle C, Hoarau M, Grierson DS et al (2002) Benzoindoloquinolines interact with DNA tetraplexes and inhibit telomerase. Bioorg Med Chem Lett 12(7):1071–1074

    Article  PubMed  CAS  Google Scholar 

  8. Riou JF, Guittat L, Mailliet P, Laoui A, Renou E, Petitgenet O et al (2002) Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands. Proc Natl Acad Sci USA 99(5):2672–2677

    Article  PubMed  CAS  Google Scholar 

  9. Mawji IA, Simpson CD, Hurren R, Gronda M, Williams MA, Filmus J et al (2007) Critical role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation. JNCI 99(10):811–822

    PubMed  CAS  Google Scholar 

  10. Carter BZ, Gronda M, Wang Z, Welsh K, Pinilla C, Andreeff M et al (2005) Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 105(10):4043–4050

    Article  PubMed  CAS  Google Scholar 

  11. Datta R, Manome Y, Taneja N, Boise LH, Weichselbaum R, Thompson CB et al (1995) Overexpression of Bcl-XL by cytotoxic drug exposure confers resistance to ionizing radiation-induced internucleosomal DNA fragmentation. Cell Growth Differ 6:363–370

    PubMed  CAS  Google Scholar 

  12. Gurfinkel DM, Chow S, Hurren R, Gronda M, Henderson C, Berube C et al (2006) Disruption of the endoplasmic reticulum and increases in cytoplasmic calcium are early events in cell death induced by the natural triterpenoid asiatic acid. Apoptosis 11(9):1463–1471

    Article  PubMed  CAS  Google Scholar 

  13. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J 19(21):5720–5728

    Article  PubMed  CAS  Google Scholar 

  14. Itoh T, Ito Y, Ohguchi K, Ohyama M, Iinuma M, Otsuki Y et al (2008) Eupalinin A isolated from Eupatorium chinense L. induces autophagocytosis in human leukemia HL60 cells. Bioorg Med Chem 16(2):721–731

    Google Scholar 

  15. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42

    Article  PubMed  CAS  Google Scholar 

  16. Sato K, Tsuchihara K, Fujii S, Sugiyama M, Goya T, Atomi Y et al (2007) Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Res 67(20):9677–9684

    Article  PubMed  CAS  Google Scholar 

  17. Hwang SO, Lee GM (2008) Nutrient deprivation induces autophagy as well as apoptosis in Chinese hamster ovary cell culture. Biotechnol Bioeng 99(3):678–685

    Article  PubMed  CAS  Google Scholar 

  18. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2007) Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J Cell Sci 120(Pt 23):4155–4166

    Article  PubMed  CAS  Google Scholar 

  19. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB (2008) Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 15(1):171–182

    Article  PubMed  CAS  Google Scholar 

  20. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB et al (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6(12):1221–1228

    Article  PubMed  CAS  Google Scholar 

  21. Miao ZH, Rao VA, Agama K, Antony S, Kohn KW, Pommier Y (2006) 4-nitroquinoline-1-oxide induces the formation of cellular topoisomerase I-DNA cleavage complexes. Cancer Res 66(13):6540–6545

    Article  PubMed  CAS  Google Scholar 

  22. Antony S, Agama KK, Miao ZH, Hollingshead M, Holbeck SL, Wright MH et al (2006) Bisindenoisoquinoline bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propyla mino}propane bis(trifluoroacetate) (NSC 727357), a DNA intercalator and topoisomerase inhibitor with antitumor activity. Mol Pharmacol 70(3):1109–1120

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Ontario Cancer Institute, Princess Margaret Hospital, 610 University Ave, Toronto, ON, Canada, M5G 2M9

    Rose Hurren, Reza Beheshti Zavareh, Shadi Dalili, Tabitha Wood, David Rose, Hong Chang, Nazir Jamal, Hans Messner & Aaron D. Schimmer

  2. The Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Reza Beheshti Zavareh, David Rose, Hans Messner & Aaron D. Schimmer

  3. The Department of Chemistry, University of Toronto, Toronto, ON, Canada

    Shadi Dalili, Tabitha Wood & Robert A. Batey

  4. The Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Hans Messner & Aaron D. Schimmer

Authors
  1. Rose Hurren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reza Beheshti Zavareh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shadi Dalili
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tabitha Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nazir Jamal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans Messner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert A. Batey
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Aaron D. Schimmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aaron D. Schimmer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hurren, R., Zavareh, R.B., Dalili, S. et al. A novel diquinolonium displays preclinical anti-cancer activity and induces caspase-independent cell death. Apoptosis 13, 748–755 (2008). https://doi.org/10.1007/s10495-008-0209-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-008-0209-6

Keywords

Search

Navigation