title: Diaryl sulfide analogs of combretastatin A-4: Toxicogenetic, immunomodulatory and apoptotic evaluations and prospects for use as a new chemotherapeutic drug.
abstract: Combretastatin A-4 exhibits efficient anti-cancer potential in human tumors, including multidrug-resistant tumors. We evaluated the mutagenic, apoptotic and immunomodulatory potential of two diaryl sulfide analogs of combretastatin A-4, 1,2,3-trimethoxy-5-([4-methoxy-3-nitrophenyl]thio)benzene (analog 1) and 1,2,3-trimethoxy-5-([3-amino-4-methoxyphenyl]thio)benzene (analog 2), as well as their association with the anti-tumor agent cyclophosphamide, in Swiss mice. Such evaluation was achieved using the comet assay, peripheral blood micronucleus test, splenic phagocytosis assay, and apoptosis assay. Both analogs were found to be genotoxic, mutagenic and to induce apoptosis. They also increased splenic phagocytosis, although this increase was more pronounced for analog 2. When combined with cyclophosphamide, analog 1 enhanced the mutagenic and apoptotic effects of this anti-tumor agent. In contrast, analog 2 did not enhance the effects of cyclophosphamide and prevented apoptosis at lower doses. These data suggest that analog 1 could be an adjuvant chemotherapeutic agent and possibly improve the anti-neoplastic effect of cyclophosphamide. Additionally, this compound could be a candidate chemotherapeutic agent and/or an adjuvant for use in combined anti-cancer therapy.
authors.affiliation: Center for Stem Cells, Cell Therapy and Genetic Toxicology Studies (Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica - CeTroGen), Maria Aparecida Pedrossian University Hospital (Hospital Universitário Maria Aparecida Pedrossian), EBSERH (Empresa Brasileira de Serviços Hospitalares), Campo Grande, Mato Grosso do Sul, Brazil; Graduate Program in Health and Development in the Midwestern Region, Medical School (Faculdade Medicina - FAMED), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Pamela Castilho
authors.initials: PC
authors.lastname: Carvalho
authors.affiliation: Biochemistry Laboratory, Center for Biological and Health Sciences, Federal University of Mato Grosso do Sul (Universidade Federal do Mato Grosso do Sul - UFMS), Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Edson Anjos
authors.initials: EA
authors.lastname: Santos
authors.affiliation: Center for Stem Cells, Cell Therapy and Genetic Toxicology Studies (Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica - CeTroGen), Maria Aparecida Pedrossian University Hospital (Hospital Universitário Maria Aparecida Pedrossian), EBSERH (Empresa Brasileira de Serviços Hospitalares), Campo Grande, Mato Grosso do Sul, Brazil; Graduate Program in Health and Development in the Midwestern Region, Medical School (Faculdade Medicina - FAMED), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Beatriz Ursinos Catelán
authors.initials: BU
authors.lastname: Schneider
authors.affiliation: Center for Stem Cells, Cell Therapy and Genetic Toxicology Studies (Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica - CeTroGen), Maria Aparecida Pedrossian University Hospital (Hospital Universitário Maria Aparecida Pedrossian), EBSERH (Empresa Brasileira de Serviços Hospitalares), Campo Grande, Mato Grosso do Sul, Brazil; Master's Program in Pharmacy, Center for Biological and Health Sciences (Centro de Ciências Biológicas e da Saúde - CCBS), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Matuo
authors.affiliation: Center for Stem Cells, Cell Therapy and Genetic Toxicology Studies (Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica - CeTroGen), Maria Aparecida Pedrossian University Hospital (Hospital Universitário Maria Aparecida Pedrossian), EBSERH (Empresa Brasileira de Serviços Hospitalares), Campo Grande, Mato Grosso do Sul, Brazil; Graduate Program in Health and Development in the Midwestern Region, Medical School (Faculdade Medicina - FAMED), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: João Renato
authors.initials: JR
authors.lastname: Pesarini
authors.affiliation: Master's Program in Pharmacy, Center for Biological and Health Sciences (Centro de Ciências Biológicas e da Saúde - CCBS), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Andréa Luiza
authors.initials: AL
authors.lastname: Cunha-Laura
authors.affiliation: Master's Program in Pharmacy, Center for Biological and Health Sciences (Centro de Ciências Biológicas e da Saúde - CCBS), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Antônio Carlos Duenhas
authors.initials: AC
authors.lastname: Monreal
authors.affiliation: Graduate Program in Chemistry, Institute of Chemistry (Instituto de Química - IQ), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Dênis Pires
authors.initials: DP
authors.lastname: Lima
authors.affiliation: Center for Stem Cells, Cell Therapy and Genetic Toxicology Studies (Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica - CeTroGen), Maria Aparecida Pedrossian University Hospital (Hospital Universitário Maria Aparecida Pedrossian), EBSERH (Empresa Brasileira de Serviços Hospitalares), Campo Grande, Mato Grosso do Sul, Brazil; Graduate Program in Health and Development in the Midwestern Region, Medical School (Faculdade Medicina - FAMED), UFMS, Campo Grande, Mato Grosso do Sul, Brazil.
authors.forename: Andréia Conceição Milan Brochado
authors.initials: AC
authors.lastname: Antoniolli
authors.affiliation: Center for Stem Cells, Cell Therapy and Genetic Toxicology Studies (Centro de Estudos em Células Tronco, Terapia Celular e Genética Toxicológica - CeTroGen), Maria Aparecida Pedrossian University Hospital (Hospital Universitário Maria Aparecida Pedrossian), EBSERH (Empresa Brasileira de Serviços Hospitalares), Campo Grande, Mato Grosso do Sul, Brazil; Graduate Program in Health and Development in the Midwestern Region, Medical School (Faculdade Medicina - FAMED), UFMS, Campo Grande, Mato Grosso do Sul, Brazil; Master's Program in Pharmacy, Center for Biological and Health Sciences (Centro de Ciências Biológicas e da Saúde - CCBS), UFMS, Campo Grande, Mato Grosso do Sul, Brazil. Electronic address: rodrigo.oliveira@ufms.br.
authors.forename: Rodrigo Juliano
authors.initials: RJ
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D010587:Phagocytosis / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry; D013440:Sulfides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D013440:Sulfides; D003520:Cyclophosphamide; D004247:DNA; C058728:fosbretabulin
keywords: Anti-neoplastic; Cancer; Chemotherapeutic; Comet assay; Micronucleus test; Sulfide