title: Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549.
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.
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Lucas Lourenço
authors.initials: LL
authors.lastname: Marostica
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Izabella Thaís
authors.initials: IT
authors.lastname: Silva
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Jadel Müller
authors.initials: JM
authors.lastname: Kratz
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Lara
authors.initials: L
authors.lastname: Persich
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Fabiana Cristina
authors.initials: FC
authors.lastname: Geller
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Karen Luise
authors.initials: KL
authors.lastname: Lang
authors.affiliation: Departamento de Química, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Miguel Soriano Balparda
authors.initials: MS
authors.lastname: Caro
authors.affiliation: UMYMFOR-CONICET, Departamento de Química Orgánica, Universidad de Buenos Aires , Buenos Aires, Argentina.
authors.forename: Fernando Javier
authors.initials: FJ
authors.lastname: Durán
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Eloir Paulo
authors.initials: EP
authors.lastname: Schenkel
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , Campus Trindade, CEP 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Cláudia Maria Oliveira
authors.initials: CM
authors.lastname: Simões
mesh_terms: D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; C495901:TP53 protein, human; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; C041246:cucurbitacin B; D000077146:Irinotecan; D017239:Paclitaxel; D002945:Cisplatin; D002166:Camptothecin