Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage
Context: Quassinoids are biologically active secondary metabolites found exclusively in the Simaroubaceae family of plants. These compounds generally present important biological properties, including cytotoxic and antitumor properties. Objective: In the present study, the cytotoxic effects of neose...
| Autor principal: | Coelho Cavalcanti, Bruno |
|---|---|
| Outros Autores: | Costa, Patrícia Marçal da, Carvalho, Adriana Andrade Carvalho, Rodrigues, Francisco Augusto Rocha Santos, Amorim, Rodrigo C.N., Silva, Ellen Cristina Costa, Pohlit, Adrian Martin, Costa-Lotufo, Leticia Veras, Moraes, Manœl Odorico de, Pessoa, Cláudia do Ó. |
| Grau: | Artigo |
| Idioma: | English |
| Publicado em: |
Pharmaceutical Biology
2020
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| Acesso em linha: |
https://repositorio.inpa.gov.br/handle/1/16120 |
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oai:repositorio:1-16120 |
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oai:repositorio:1-16120 Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage Coelho Cavalcanti, Bruno Costa, Patrícia Marçal da Carvalho, Adriana Andrade Carvalho Rodrigues, Francisco Augusto Rocha Santos Amorim, Rodrigo C.N. Silva, Ellen Cristina Costa Pohlit, Adrian Martin Costa-Lotufo, Leticia Veras Moraes, Manœl Odorico de Pessoa, Cláudia do Ó. Antineoplastic Agent Caspase 3 Caspase 7 Caspase 9 Cyclosporin A Doxorubicin Neosergeolide Phosphatidylserine Quassinoid Derivative Reactive Oxygen Metabolite Unclassified Drug Antiproliferative Activity Apoptosis Cancer Inhibition Cell Cycle G0 Phase Cell Cycle G1 Phase Cell Cycle G2 Phase Cell Cycle M Phase Cell Cycle S Phase Cell Differentiation Cell Proliferation Cell Strain Hl 60 Cell Structure Cell Viability Concentration Response Controlled Study Depolarization Dna Content Dna Damage Dna Fragmentation Drug Effect Drug Mechanism Enzyme Activation Genotoxicity Human Human Cell Ic 50 Leukemia Cell Membrane Potential, Mitochondrial Mitochondrial Permeability Mutagenic Activity Oxidative Stress Peripheral Blood Mononuclear Cell Promyelocytic Leukemia Antineoplastic Agents, Phytogenic Apoptosis Cell Proliferation Cells, Cultured Comet Assay Cyclosporine Cytokinesis Dna Fragmentation Hl-60 Cells Humans Inhibitory Concentration 50 Leukemia, Promyelocytic, Acute Leukocytes, Mononuclear Membrane Potential, Mitochondrial Micronucleus Tests Mitochondria Mitochondrial Membrane Transport Proteins Neoplasm Proteins Quassins Simaroubaceae Picrolemma Simaroubaceae Context: Quassinoids are biologically active secondary metabolites found exclusively in the Simaroubaceae family of plants. These compounds generally present important biological properties, including cytotoxic and antitumor properties. Objective: In the present study, the cytotoxic effects of neosergeolide, a quassinoid isolated from Picrolemma sprucei Hook. f., were evaluated in human promyelocytic leukemia cells (HL-60). Materials and methods: Cytotoxicity and antiproliferative effects were evaluated by the MTT assay, May-Grünwald-Giemsa's staining, BrdU incorporation test, and flow cytometry procedures. The comet assay and micronuclei analysis were applied to determine the genotoxic and mutagenic potential of neosergeolide. Results: After 24h exposure, neosergeolide strongly inhibited cancer cell proliferation (IC 50 0.1 μM), and its activity seemed to be selective to tumor cells because it had no antiproliferative effect on human peripheral blood mononuclear cells (PBMC) at tested concentrations. Apoptosis was induced at submicromolar concentrations (0.05, 0.1, and 0.2 μM) as evidenced by morphological changes, mitochondrial depolarization, phosphatidylserine externalization, caspases activation, and internucleosomal DNA fragmentation. Additionally, neosergeolide effects were prevented by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition (MPT) pore, which reinforced the participation of intrinsic pathways in the apoptotic process induced by this natural quassinoid. Direct DNA damage was further confirmed by comet assay and cytokinesis-block micronucleus test. Discussion and conclusion: The present study provided experimental evidence to support the underlying mechanism of action involved in the neosergeolide-mediated apoptosis. In addition, no antiproliferative effect or DNA damage effect of neosergeolide was evident in PBMC, highlighting its therapeutic potential. © 2012 Informa Healthcare USA, Inc. 2020-05-24T21:49:10Z 2020-05-24T21:49:10Z 2012 Artigo https://repositorio.inpa.gov.br/handle/1/16120 10.3109/13880209.2012.654921 en Volume 50, Número 8, Pags. 980-993 Attribution-NonCommercial-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nc-nd/3.0/br/ application/pdf Pharmaceutical Biology |
| institution |
Instituto Nacional de Pesquisas da Amazônia - Repositório Institucional |
| collection |
INPA-RI |
| language |
English |
| topic |
Antineoplastic Agent Caspase 3 Caspase 7 Caspase 9 Cyclosporin A Doxorubicin Neosergeolide Phosphatidylserine Quassinoid Derivative Reactive Oxygen Metabolite Unclassified Drug Antiproliferative Activity Apoptosis Cancer Inhibition Cell Cycle G0 Phase Cell Cycle G1 Phase Cell Cycle G2 Phase Cell Cycle M Phase Cell Cycle S Phase Cell Differentiation Cell Proliferation Cell Strain Hl 60 Cell Structure Cell Viability Concentration Response Controlled Study Depolarization Dna Content Dna Damage Dna Fragmentation Drug Effect Drug Mechanism Enzyme Activation Genotoxicity Human Human Cell Ic 50 Leukemia Cell Membrane Potential, Mitochondrial Mitochondrial Permeability Mutagenic Activity Oxidative Stress Peripheral Blood Mononuclear Cell Promyelocytic Leukemia Antineoplastic Agents, Phytogenic Apoptosis Cell Proliferation Cells, Cultured Comet Assay Cyclosporine Cytokinesis Dna Fragmentation Hl-60 Cells Humans Inhibitory Concentration 50 Leukemia, Promyelocytic, Acute Leukocytes, Mononuclear Membrane Potential, Mitochondrial Micronucleus Tests Mitochondria Mitochondrial Membrane Transport Proteins Neoplasm Proteins Quassins Simaroubaceae Picrolemma Simaroubaceae |
| spellingShingle |
Antineoplastic Agent Caspase 3 Caspase 7 Caspase 9 Cyclosporin A Doxorubicin Neosergeolide Phosphatidylserine Quassinoid Derivative Reactive Oxygen Metabolite Unclassified Drug Antiproliferative Activity Apoptosis Cancer Inhibition Cell Cycle G0 Phase Cell Cycle G1 Phase Cell Cycle G2 Phase Cell Cycle M Phase Cell Cycle S Phase Cell Differentiation Cell Proliferation Cell Strain Hl 60 Cell Structure Cell Viability Concentration Response Controlled Study Depolarization Dna Content Dna Damage Dna Fragmentation Drug Effect Drug Mechanism Enzyme Activation Genotoxicity Human Human Cell Ic 50 Leukemia Cell Membrane Potential, Mitochondrial Mitochondrial Permeability Mutagenic Activity Oxidative Stress Peripheral Blood Mononuclear Cell Promyelocytic Leukemia Antineoplastic Agents, Phytogenic Apoptosis Cell Proliferation Cells, Cultured Comet Assay Cyclosporine Cytokinesis Dna Fragmentation Hl-60 Cells Humans Inhibitory Concentration 50 Leukemia, Promyelocytic, Acute Leukocytes, Mononuclear Membrane Potential, Mitochondrial Micronucleus Tests Mitochondria Mitochondrial Membrane Transport Proteins Neoplasm Proteins Quassins Simaroubaceae Picrolemma Simaroubaceae Coelho Cavalcanti, Bruno Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage |
| topic_facet |
Antineoplastic Agent Caspase 3 Caspase 7 Caspase 9 Cyclosporin A Doxorubicin Neosergeolide Phosphatidylserine Quassinoid Derivative Reactive Oxygen Metabolite Unclassified Drug Antiproliferative Activity Apoptosis Cancer Inhibition Cell Cycle G0 Phase Cell Cycle G1 Phase Cell Cycle G2 Phase Cell Cycle M Phase Cell Cycle S Phase Cell Differentiation Cell Proliferation Cell Strain Hl 60 Cell Structure Cell Viability Concentration Response Controlled Study Depolarization Dna Content Dna Damage Dna Fragmentation Drug Effect Drug Mechanism Enzyme Activation Genotoxicity Human Human Cell Ic 50 Leukemia Cell Membrane Potential, Mitochondrial Mitochondrial Permeability Mutagenic Activity Oxidative Stress Peripheral Blood Mononuclear Cell Promyelocytic Leukemia Antineoplastic Agents, Phytogenic Apoptosis Cell Proliferation Cells, Cultured Comet Assay Cyclosporine Cytokinesis Dna Fragmentation Hl-60 Cells Humans Inhibitory Concentration 50 Leukemia, Promyelocytic, Acute Leukocytes, Mononuclear Membrane Potential, Mitochondrial Micronucleus Tests Mitochondria Mitochondrial Membrane Transport Proteins Neoplasm Proteins Quassins Simaroubaceae Picrolemma Simaroubaceae |
| description |
Context: Quassinoids are biologically active secondary metabolites found exclusively in the Simaroubaceae family of plants. These compounds generally present important biological properties, including cytotoxic and antitumor properties. Objective: In the present study, the cytotoxic effects of neosergeolide, a quassinoid isolated from Picrolemma sprucei Hook. f., were evaluated in human promyelocytic leukemia cells (HL-60). Materials and methods: Cytotoxicity and antiproliferative effects were evaluated by the MTT assay, May-Grünwald-Giemsa's staining, BrdU incorporation test, and flow cytometry procedures. The comet assay and micronuclei analysis were applied to determine the genotoxic and mutagenic potential of neosergeolide. Results: After 24h exposure, neosergeolide strongly inhibited cancer cell proliferation (IC 50 0.1 μM), and its activity seemed to be selective to tumor cells because it had no antiproliferative effect on human peripheral blood mononuclear cells (PBMC) at tested concentrations. Apoptosis was induced at submicromolar concentrations (0.05, 0.1, and 0.2 μM) as evidenced by morphological changes, mitochondrial depolarization, phosphatidylserine externalization, caspases activation, and internucleosomal DNA fragmentation. Additionally, neosergeolide effects were prevented by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition (MPT) pore, which reinforced the participation of intrinsic pathways in the apoptotic process induced by this natural quassinoid. Direct DNA damage was further confirmed by comet assay and cytokinesis-block micronucleus test. Discussion and conclusion: The present study provided experimental evidence to support the underlying mechanism of action involved in the neosergeolide-mediated apoptosis. In addition, no antiproliferative effect or DNA damage effect of neosergeolide was evident in PBMC, highlighting its therapeutic potential. © 2012 Informa Healthcare USA, Inc. |
| format |
Artigo |
| author |
Coelho Cavalcanti, Bruno |
| author2 |
Costa, Patrícia Marçal da Carvalho, Adriana Andrade Carvalho Rodrigues, Francisco Augusto Rocha Santos Amorim, Rodrigo C.N. Silva, Ellen Cristina Costa Pohlit, Adrian Martin Costa-Lotufo, Leticia Veras Moraes, Manœl Odorico de Pessoa, Cláudia do Ó. |
| author2Str |
Costa, Patrícia Marçal da Carvalho, Adriana Andrade Carvalho Rodrigues, Francisco Augusto Rocha Santos Amorim, Rodrigo C.N. Silva, Ellen Cristina Costa Pohlit, Adrian Martin Costa-Lotufo, Leticia Veras Moraes, Manœl Odorico de Pessoa, Cláudia do Ó. |
| title |
Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage |
| title_short |
Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage |
| title_full |
Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage |
| title_fullStr |
Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage |
| title_full_unstemmed |
Involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human HL-60 leukemia cells: The role of mitochondrial permeability transition pore and DNA damage |
| title_sort |
involvement of intrinsic mitochondrial pathway in neosergeolide-induced apoptosis of human hl-60 leukemia cells: the role of mitochondrial permeability transition pore and dna damage |
| publisher |
Pharmaceutical Biology |
| publishDate |
2020 |
| url |
https://repositorio.inpa.gov.br/handle/1/16120 |
| _version_ |
1787141312515932160 |
| score |
11.755432 |