Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 4; pp. 958 - 967
• Main Authors: Vieira Torquato, Heron F., Ribeiro-Filho, Antonio C., Buri, Marcus V., Araújo Júnior, Roberto T., Pimenta, Renata, de Oliveira, José Salvador R., Filho, Valdir C., Macho, Antonio, Paredes-Gamero, Edgar J., de Oliveira Martins, Domingos T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2017
• Subjects: antineoplastic activity; apoptosis; Apoptosis - drug effects; Biomarkers, Tumor - metabolism; Canthin-6-one; Carbolines - pharmacology; caspases; Cell cycle arrest; cell cycle checkpoints; Cell Cycle Checkpoints - drug effects; Cell death; Cell Death - drug effects; Cell differentiation; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Lineage - drug effects; cyclins; cytotoxicity; DNA; fungi; Gene Expression Regulation, Leukemic - drug effects; Humans; Indole Alkaloids - pharmacology; K562 Cells; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemic stem cells; mitochondria; Myeloid Cells - drug effects; Myeloid Cells - metabolism; myeloid leukemia; neoplasm cells; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; propidium; stem cells; transcription factors; Cell cycle arrest; Cell differentiation; Cell death; Leukemia; Leukemic stem cells; Canthin-6-one
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.01.033

Canthin-6-one is a natural product isolated from various plant genera and from fungi with potential antitumor activity. In the present study, we evaluate the antitumor effects of canthin-6-one in human myeloid leukemia lineages. Kasumi-1 lineage was used as a model for acute myeloid leukemia. Cells were treated with canthin-6-one and cell death, cell cycle and differentiation were evaluated in both total cells (Lin+) and leukemia stem cell population (CD34+CD38−Lin−/low). Among the human lineages tested, Kasumi-1 was the most sensitive to canthin-6-one. Canthin-6-one induced cell death with apoptotic (caspase activation, decrease of mitochondrial potential) and necrotic (lysosomal permeabilization, double labeling of annexin V/propidium iodide) characteristics. Moreover, canthin-6-one induced cell cycle arrest at G0/G1 (7μM) and G2 (45μM) evidenced by DNA content, BrdU incorporation and cyclin B1/histone 3 quantification. Canthin-6-one also promoted differentiation of Kasumi-1, evidenced by an increase in the expression of myeloid markers (CD11b and CD15) and the transcription factor PU.1. Furthermore, a reduction of the leukemic stem cell population and clonogenic capability of stem cells were observed. These results show that canthin-6-one can affect Kasumi-1 cells by promoting cell death, cell cycle arrest and cell differentiation depending on concentration used. Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity. [Display omitted] •Canthin-6-one induces cell death with apoptotic and necrotic characteristics in AML cell line.•Cell cycle arrest induced by canthin-6-one was concentration-dependent.•Canthin-6-one reduces leukemic stem cell population and elicits cell differentiation in AML lineages.