Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells.
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.
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.
Heron F
HF
Vieira Torquato
Centro Interdisciplinar de Investigação Bioquı́mica, Universidade de Mogi das Cruzes, Av. Dr. Cândido Xavier de Almeida Souza, 200, Mogi das Cruzes, São Paulo, Brazil.
Antonio C
AC
Ribeiro-Filho
Department of Biochemistry, Federal University of São Paulo (UNIFESP), Av. Pedro de Toledo, no. 669, São Paulo, São Paulo 04039-401, Brazil.
Marcus V
MV
Buri
Department of Biochemistry, Federal University of São Paulo (UNIFESP), Av. Pedro de Toledo, no. 669, São Paulo, São Paulo 04039-401, Brazil.
Roberto T
RT
Araújo Júnior
Department of Medicine (Hematology), Federal University of São Paulo (UNIFESP), Av. Diogo de Faria, 824, São Paulo, São Paulo 04037-002, Brazil.
Renata
R
Pimenta
Department of Medicine (Hematology), Federal University of São Paulo (UNIFESP), Av. Diogo de Faria, 824, São Paulo, São Paulo 04037-002, Brazil.
José Salvador R
JS
de Oliveira
Chemical-Pharmaceutical Research Center, University of Vale of Itajaí (UNIVALI), Rua Uruguai, no. 458, Centro, Itajaí, Santa Catarina 88302-202, Brazil.
Valdir C
VC
Filho
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.
Antonio
A
Macho
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.
Edgar J
EJ
Paredes-Gamero
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.
Domingos T
DT
de Oliveira Martins
D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism
D014408:Biomarkers, Tumor; D002243:Carbolines; D026121:Indole Alkaloids; C453379:canthin-6-one
Canthin-6-one; Cell cycle arrest; Cell death; Cell differentiation; Leukemia; Leukemic stem cells