Abstract:
Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer. © 2015 American Chemical Society.
Registro:
Documento: |
Artículo
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Título: | Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
Autor: | Marostica, L.L.; Silva, I.T.; Kratz, J.M.; Persich, L.; Geller, F.C.; Lang, K.L.; Caro, M.S.B.; Durán, F.J.; Schenkel, E.P.; Simões, C.M.O. |
Filiación: | Departamento de Cieîncias Farmaceîuticas, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, Santa Catarina CEP 88040-900, Brazil Departamento de Química, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, Santa Catarina CEP 88040-900, Brazil UMYMFOR-CONICET, Departamento de Química Orgánica, Universidad de Buenos AiresBuenos Aires, Argentina
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Palabras clave: | 2 deoxy 2 amine cucurbitacin E; acetylcysteine; buthionine sulfoximine; caspase; cisplatin; cucurbitacin; F actin; irinotecan; paclitaxel; protein p53; reactive oxygen metabolite; survivin; unclassified drug; actin; antineoplastic agent; BIRC5 protein, human; camptothecin; cisplatin; cucurbitacin B; inhibitor of apoptosis protein; irinotecan; paclitaxel; protein p53; reactive oxygen metabolite; TP53 protein, human; triterpene; A549 cell line; antiproliferative activity; apoptosis; Article; cancer inhibition; cell proliferation; comparative effectiveness; computer model; controlled study; cytoskeleton; drug mechanism; drug potency; drug potentiation; drug structure; enzyme activity; enzyme inhibition; flow cytometry; G2 phase cell cycle checkpoint; human; human cell; IC50; metastasis inhibition; migration inhibition; protein expression; analogs and derivatives; cell motion; chemistry; drug effects; Lung Neoplasms; M phase cell cycle checkpoint; metabolism; pathology; tumor cell line; Actins; Antineoplastic Agents; Apoptosis; Camptothecin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Drug Synergism; G2 Phase Cell Cycle Checkpoints; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Paclitaxel; Reactive Oxygen Species; Triterpenes; Tumor Suppressor Protein p53 |
Año: | 2015
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Volumen: | 28
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Número: | 10
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Página de inicio: | 1949
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Página de fin: | 1960
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DOI: |
http://dx.doi.org/10.1021/acs.chemrestox.5b00153 |
Título revista: | Chemical Research in Toxicology
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Título revista abreviado: | Chem. Res. Toxicol.
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ISSN: | 0893228X
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CODEN: | CRTOE
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CAS: | acetylcysteine, 616-91-1; buthionine sulfoximine, 5072-26-4; caspase, 186322-81-6; cisplatin, 15663-27-1, 26035-31-4, 96081-74-2; F actin, 39409-31-9; irinotecan, 100286-90-6; paclitaxel, 33069-62-4; survivin, 195263-98-0; camptothecin, 7689-03-4; Actins; Antineoplastic Agents; BIRC5 protein, human; Camptothecin; Cisplatin; cucurbitacin B; Inhibitor of Apoptosis Proteins; irinotecan; Paclitaxel; Reactive Oxygen Species; TP53 protein, human; Triterpenes; Tumor Suppressor Protein p53
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0893228X_v28_n10_p1949_Marostica |
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Citas:
---------- APA ----------
Marostica, L.L., Silva, I.T., Kratz, J.M., Persich, L., Geller, F.C., Lang, K.L., Caro, M.S.B.,..., Simões, C.M.O.
(2015)
. Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549. Chemical Research in Toxicology, 28(10), 1949-1960.
http://dx.doi.org/10.1021/acs.chemrestox.5b00153---------- CHICAGO ----------
Marostica, L.L., Silva, I.T., Kratz, J.M., Persich, L., Geller, F.C., Lang, K.L., et al.
"Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549"
. Chemical Research in Toxicology 28, no. 10
(2015) : 1949-1960.
http://dx.doi.org/10.1021/acs.chemrestox.5b00153---------- MLA ----------
Marostica, L.L., Silva, I.T., Kratz, J.M., Persich, L., Geller, F.C., Lang, K.L., et al.
"Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549"
. Chemical Research in Toxicology, vol. 28, no. 10, 2015, pp. 1949-1960.
http://dx.doi.org/10.1021/acs.chemrestox.5b00153---------- VANCOUVER ----------
Marostica, L.L., Silva, I.T., Kratz, J.M., Persich, L., Geller, F.C., Lang, K.L., et al. Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549. Chem. Res. Toxicol. 2015;28(10):1949-1960.
http://dx.doi.org/10.1021/acs.chemrestox.5b00153