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Biochim Biophys Acta Gen Subj. 2017 Apr;1861(4):958-967. doi: 10.1016/j.bbagen.2017.01.033. Epub 2017 Feb 2.

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

Author information

1
Department of Basic Sciences in Health, Faculty of Medicine, Federal University of Mato Grosso (UFMT), Av. Fernando Correa da Costa, no. 2367, Boa Esperança, Cuiabá, Mato Grosso 78060-900, Brazil; Department of Biochemistry, Federal University of São Paulo (UNIFESP), Av. Pedro de Toledo, no. 669, São Paulo, São Paulo 04039-401, Brazil.
2
Centro Interdisciplinar de Investigação Bioquı́mica, Universidade de Mogi das Cruzes, Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, São Paulo, Brazil.
3
Department of Biochemistry, Federal University of São Paulo (UNIFESP), Av. Pedro de Toledo, no. 669, São Paulo, São Paulo 04039-401, Brazil.
4
Department of Medicine (Hematology), Federal University of São Paulo (UNIFESP), Av. Diogo de Faria, 824, São Paulo, São Paulo 04037-002, Brazil.
5
Chemical-Pharmaceutical Research Center, University of Vale of Itajaí (UNIVALI), Rua Uruguai, no. 458, Centro, Itajaí, Santa Catarina 88302-202, Brazil.
6
Department of Basic Sciences in Health, Faculty of Medicine, Federal University of Mato Grosso (UFMT), Av. Fernando Correa da Costa, no. 2367, Boa Esperança, Cuiabá, Mato Grosso 78060-900, Brazil.
7
Department of Biochemistry, Federal University of São Paulo (UNIFESP), Av. Pedro de Toledo, no. 669, São Paulo, São Paulo 04039-401, Brazil; Centro Interdisciplinar de Investigação Bioquı́mica, Universidade de Mogi das Cruzes, Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, São Paulo, Brazil. Electronic address: paredes.gamero@gmail.com.
8
Department of Basic Sciences in Health, Faculty of Medicine, Federal University of Mato Grosso (UFMT), Av. Fernando Correa da Costa, no. 2367, Boa Esperança, Cuiabá, Mato Grosso 78060-900, Brazil. Electronic address: taba@terra.com.br.

Abstract

BACKGROUND:

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.

METHODS:

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).

RESULTS:

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.

CONCLUSIONS:

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.

GENERAL SIGNIFICANCE:

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.

KEYWORDS:

Canthin-6-one; Cell cycle arrest; Cell death; Cell differentiation; Leukemia; Leukemic stem cells

PMID:
28161479
DOI:
10.1016/j.bbagen.2017.01.033
[Indexed for MEDLINE]
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