Oxindole alkaloids from Uncaria tomentosa induce apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells.
Natural products are still an untapped source of promising lead compounds for the generation of antineoplastic drugs. Here, we investigated for the first time the antiproliferative and apoptotic effects of highly purified oxindole alkaloids, namely isopteropodine (A1), pteropodine (A2), isomitraphylline (A3), uncarine F (A4) and mitraphylline (A5) obtained from Uncaria tomentosa, a South American Rubiaceae, on human lymphoblastic leukaemia T cells (CCRF-CEM-C7H2). Four of the five tested alkaloids inhibited proliferation of acute lymphoblastic leukaemia cells. Furthermore, the antiproliferative effect of the most potent alkaloids pteropodine (A2) and uncarine F (A4) correlated with induction of apoptosis. After 48 h, 100 micromol/l A2 or A4 increased apoptotic cells by 57%. CEM-C7H2 sublines with tetracycline-regulated expression of bcl-2, p16ink4A or constitutively expressing the cowpox virus protein crm-A were used for further studies of the apoptosis-inducing properties of these alkaloids. Neither overexpression of bcl-2 or crm-A nor cell-cycle arrest in G0/G1 phase by tetracycline-regulated expression of p16INK4A could prevent alkaloid-induced apoptosis. Our results show the strong apoptotic effects of pteropodine and uncarine F on acute leukaemic lymphoblasts and recommend the alkaloids for further studies in xenograft models.
Bacher
Nicole
N
Department of Internal Medicine, Medical University of Innsbruck, Innsbruck, Austria.
Tiefenthaler
Martin
M
Sturm
Sonja
S
Stuppner
Hermann
H
Ausserlechner
Michael J
MJ
Kofler
Reinhard
R
Konwalinka
Günther
G
D000470:Alkaloids / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D053453:Caspase 9; D020169:Caspases / Q000032:analysis; D020948:Cat's Claw; D049109:Cell Proliferation / Q000187:drug effects; D024161:Collagen Type XI / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D026121:Indole Alkaloids / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D000078183:Oxindoles; D008517:Phytotherapy / Q000379:methods*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D013141:Spiro Compounds / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism
D000470:Alkaloids; C499319:COL11A2 protein, human; D024161:Collagen Type XI; D019941:Cyclin-Dependent Kinase Inhibitor p16; D026121:Indole Alkaloids; D007211:Indoles; D000078183:Oxindoles; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D013141:Spiro Compounds; D014764:Viral Proteins; C509328:mitraphylline; C074641:interleukin-1beta-converting enzyme inhibitor; C509327:uncarine F; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; C431786:uncarine E; C431785:uncarine C; C509329:isomitraphylline