Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549
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 candid...
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2015
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0893228X_v28_n10_p1949_Marostica http://hdl.handle.net/20.500.12110/paper_0893228X_v28_n10_p1949_Marostica |
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paper:paper_0893228X_v28_n10_p1949_Marostica2023-06-08T15:47:30Z Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 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 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. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0893228X_v28_n10_p1949_Marostica http://hdl.handle.net/20.500.12110/paper_0893228X_v28_n10_p1949_Marostica |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
| topic_facet |
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 |
| description |
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. |
| title |
Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
| title_short |
Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
| title_full |
Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
| title_fullStr |
Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
| title_full_unstemmed |
Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549 |
| title_sort |
synergistic antiproliferative effects of a new cucurbitacin b derivative and chemotherapy drugs on lung cancer cell line a549 |
| publishDate |
2015 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0893228X_v28_n10_p1949_Marostica http://hdl.handle.net/20.500.12110/paper_0893228X_v28_n10_p1949_Marostica |
| _version_ |
1768545562828734464 |