title: Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.
abstract: Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, IUCS-Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, Gandra 4585-116, Portugal. j.filipebarbosa@hotmail.com.
authors.forename: João
authors.initials: J
authors.lastname: Barbosa
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal. rlima@ipatimup.pt.|Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto 4200-135, Portugal. rlima@ipatimup.pt.|Department of Pathology and Oncology, FMUP-Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, Porto 4200-319, Portugal. rlima@ipatimup.pt.
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal. dsousa@ipatimup.pt.|Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto 4200-135, Portugal. dsousa@ipatimup.pt.|Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. dsousa@ipatimup.pt.
authors.forename: Diana
authors.initials: D
authors.lastname: Sousa
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. anasarag4@gmail.com.|UCIBIO/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. anasarag4@gmail.com.
authors.forename: Ana Sara
authors.initials: AS
authors.lastname: Gomes
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. andreiapalmeira@gmail.com.
authors.forename: Andreia
authors.initials: A
authors.lastname: Palmeira
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal. hteixeira@ipatimup.pt.|Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto 4200-135, Portugal. hteixeira@ipatimup.pt.
authors.forename: Hugo
authors.initials: H
authors.lastname: Seca
authors.affiliation: Faculty of Medicinal Technology, Rangsit University, 52/347 Muang Ake, Phaholyothin Road, Lakhok, Pathumthani 10210, Thailand. kantima90@hotmail.com.
authors.forename: Kantima
authors.initials: K
authors.lastname: Choosang
authors.affiliation: Applied Radiation and Isotopes Department, Faculty of Science, Kasetsart University, Jatujak, Bangkok 10930, Thailand. fscipnp@ku.ac.th.
authors.forename: Pannee
authors.initials: P
authors.lastname: Pakkong
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, IUCS-Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, Gandra 4585-116, Portugal. hbousbaa@gmail.com.
authors.forename: Hassan
authors.initials: H
authors.lastname: Bousbaa
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. madalena@ff.up.pt.|CIIMAR/CIMAR-Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas 289, Porto 4050-123, Portugal. madalena@ff.up.pt.
authors.forename: Madalena M
authors.initials: MM
authors.lastname: Pinto
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. esousa@ff.up.pt.|CIIMAR/CIMAR-Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas 289, Porto 4050-123, Portugal. esousa@ff.up.pt.
authors.forename: Emília
authors.initials: E
authors.lastname: Sousa
authors.affiliation: i3S-Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal. hvasconcelos@ipatimup.pt.|Cancer Drug Resistance Group, IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto 4200-135, Portugal. hvasconcelos@ipatimup.pt.|Laboratory of Microbiology, Department of Biological Sciences, FFUP-Faculty of Pharmacy of the University of Porto, Rua de Jorge Viterbo Ferreira 228, Porto 4050-313, Portugal. hvasconcelos@ipatimup.pt.
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
authors.affiliation: CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, IUCS-Instituto Universitário de Ciências da Saúde, Rua Central de Gandra 1317, Gandra 4585-116, Portugal. madalena.oliveira.pedro@gmail.com.
authors.forename: Madalena
authors.initials: M
authors.lastname: Pedro
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013892:Thioxanthenes / Q000138:chemical synthesis / Q000494:pharmacology*; D044004:Xanthones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D013892:Thioxanthenes; D044004:Xanthones
keywords: antitumor activity screening; apoptosis; in vitro cell growth assays; thioxanthones