title: Prenylated Chalcone 2 Acts as an Antimitotic Agent and Enhances the Chemosensitivity of Tumor Cells to Paclitaxel.
abstract: We previously reported that prenylated chalcone 2 (PC2), the O-prenyl derivative (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1), induced cytotoxicity of tumor cells via disruption of p53-MDM2 interaction. However, the cellular changes through which PC2 exerts its cytotoxic activity and its antitumor potential, remain to be addressed. In the present work, we aimed to (i) characterize the effect of PC2 on mitotic progression and the underlying mechanism; and to (ii) explore this information to evaluate its ability to sensitize tumor cells to paclitaxel in a combination regimen. PC2 was able to arrest breast adenocarcinoma MCF-7 and non-small cell lung cancer NCI-H460 cells in mitosis. All mitosis-arrested cells showed collapsed mitotic spindles with randomly distributed chromosomes, and activated spindle assembly checkpoint. Live-cell imaging revealed that the compound induced a prolonged delay (up to 14 h) in mitosis, culminating in massive cell death by blebbing. Importantly, PC2 in combination with paclitaxel enhanced the effect on cell growth inhibition as determined by cell viability and proliferation assays. Our findings demonstrate that the cytotoxicity induced by PC2 is mediated through antimitotic activity as a result of mitotic spindle damage. The enhancement effects of PC2 on chemosensitivity of cancer cells to paclitaxel encourage further validation of the clinical potential of this combination.
authors.affiliation: CESPU, Instituto de Investiga&#231;&#227;o e Forma&#231;&#227;o Avan&#231;ada em Ci&#234;ncias e Tecnologias da Sa&#250;de, IINFACTS, 4585-116 Gandra PRD, Portugal. joanafonsecabioq@hotmail.com.
authors.forename: Joana
authors.initials: J
authors.lastname: Fonseca
authors.affiliation: CESPU, Instituto de Investiga&#231;&#227;o e Forma&#231;&#227;o Avan&#231;ada em Ci&#234;ncias e Tecnologias da Sa&#250;de, IINFACTS, 4585-116 Gandra PRD, Portugal. marques.sandra075@gmail.com.
authors.forename: Sandra
authors.initials: S
authors.lastname: Marques
authors.affiliation: CESPU, Instituto de Investiga&#231;&#227;o e Forma&#231;&#227;o Avan&#231;ada em Ci&#234;ncias e Tecnologias da Sa&#250;de, IINFACTS, 4585-116 Gandra PRD, Portugal. patricia_masilva@hotmail.com.|Center for Biomedical Research, CBMR, University of Algarve, 8005-139 Faro, Portugal. patricia_masilva@hotmail.com.|Departamento Ci&#234;ncias Biom&#233;dicas e Medicina, University of Algarve, 8005-139 Faro, Portugal. patricia_masilva@hotmail.com.
authors.forename: Patrícia M A
authors.initials: PM
authors.lastname: Silva
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Org&#226;nica e Farmac&#234;utica, Departamento de Ci&#234;ncias Qu&#237;micas, Faculdade de Farm&#225;cia, Universidade do Porto, 4050-313 Porto, Portugal. pedrocgbrandao@gmail.com.
authors.forename: Pedro
authors.initials: P
authors.lastname: Brandão
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Org&#226;nica e Farmac&#234;utica, Departamento de Ci&#234;ncias Qu&#237;micas, Faculdade de Farm&#225;cia, Universidade do Porto, 4050-313 Porto, Portugal. hcidade@ff.up.pt.|Centro Interdisciplinar de Investiga&#231;&#227;o Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, 4050-123 Porto, Portugal. hcidade@ff.up.pt.
authors.forename: Honorina
authors.initials: H
authors.lastname: Cidade
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Org&#226;nica e Farmac&#234;utica, Departamento de Ci&#234;ncias Qu&#237;micas, Faculdade de Farm&#225;cia, Universidade do Porto, 4050-313 Porto, Portugal. madalena@ff.up.pt.|Centro Interdisciplinar de Investiga&#231;&#227;o Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, 4050-123 Porto, Portugal. madalena@ff.up.pt.
authors.forename: Madalena M
authors.initials: MM
authors.lastname: Pinto
authors.affiliation: CESPU, Instituto de Investiga&#231;&#227;o e Forma&#231;&#227;o Avan&#231;ada em Ci&#234;ncias e Tecnologias da Sa&#250;de, IINFACTS, 4585-116 Gandra PRD, Portugal. hassan.bousbaa@iscsn.cespu.pt.|Centro Interdisciplinar de Investiga&#231;&#227;o Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, 4050-123 Porto, Portugal. hassan.bousbaa@iscsn.cespu.pt.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bousbaa
mesh_terms: D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D054876:Prenylation; D008941:Spindle Apparatus / Q000378:metabolism
chemical_list: D002599:Chalcone; D017239:Paclitaxel
keywords: antimitotic; apoptosis; cancer chemotherapy; drug resistance; mitotic spindle damage; paclitaxel chemosensitivity; prenylchalcone