title: A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells.
abstract: Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumor lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression.
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, 4200-465 Porto, Portugal; ICBAS-UP - Institute of Biomedical Sciences Abel Salazar, University of Porto, ICBAS-UP, 4099-003 Porto, Portugal.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lopes-Rodrigues
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Oliveira
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR - Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Correia-da-Silva
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR - Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Portugal.
authors.forename: Madalena
authors.initials: M
authors.lastname: Pinto
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, 4200-465 Porto, Portugal; Department of Pathology and Oncology, FMUP - Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.affiliation: Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; CIIMAR/CIMAR - Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Portugal. Electronic address: esousa@ff.up.pt.
authors.forename: Emília
authors.initials: E
authors.lastname: Sousa
authors.affiliation: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Cancer Drug Resistance Group, IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, IPATIMUP, 4200-465 Porto, Portugal; Department of Biological Sciences, FFUP - Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal. Electronic address: hvasconcelos@ipatimup.pt.
authors.forename: M Helena
authors.initials: MH
authors.lastname: Vasconcelos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003474:Curcumin
keywords: Antitumor; Curcumin; Curcumin derivatives; Multidrug resistance; P-glycoprotein inhibition