A novel diquinolonium displays preclinical anti-cancer activity and induces caspase-independent cell death
Tóm tắt
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.
Tài liệu tham khảo
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
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
Nunoshiba T, Demple B (1993) Potent intracellular oxidative stress exerted by the carcinogen 4-nitroquinoline-N-oxide. Cancer Res 53(14):3250–3252
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
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
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
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
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
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
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
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
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
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
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
Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42
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
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
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
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
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
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
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