title: New 3-alkylpyridine marine alkaloid analogues as promising antitumor agents against the CD44+/high/CD24-/lowsubset of triple-negative breast cancer cell line.
abstract: Triple-negative breast cancer (TNBC) is one of the most aggressive cancers in women. Additionally, presence of residual cancer stem cells (CSC) in TNBC has challenged the efficacy of chemotherapy. Thus, the development of new molecules with potential action against CSC is fundamental. In this study, six synthetic analogues of theonelladin C, a 3-alkylpyridine marine alkaloid, were tested for cytotoxic activity against human TNBC cell line (BT-549) and tumorspheres derived from BT-549. Cytotoxicity assay was performed by sulforhodamine B (SRB). BT-549 and tumorspheres were examined for CD44+/high/CD24-/lowmarkers, indicative of CSC profile, by flow cytometry. Clonogenic assay was performed to verify inhibiting growth of tumorspheres by the synthetic analogues. Cell death by apoptosis was investigated employing annexin V assay. SRB assay on BT-549 cells revealed that compounds 1c and 2c were the most active of the series, with IC50values of 18.66 and 9.8 μm, respectively. Compounds 1c and 2c were able to reduce both CSC-like population (CD44+/high/CD24-/low) and non-CSC population (CD44+/high/CD24+/high) in tumorsphere model. Clonogenic and annexin V assays confirmed the ability of 1c and 2c to induce growth inhibition and apoptosis in BT-549 cells and tumorspheres. These preliminary data indicate that these compounds are a promising class for development of anticancer agents.
authors.affiliation: Serviço de Biologia Celular, Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil.
authors.forename: Aline Brito
authors.initials: AB
authors.lastname: de Lima
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Divinópolis, MG, Brazil.
authors.forename: Camila de Souza
authors.initials: CS
authors.lastname: Barbosa
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Divinópolis, MG, Brazil.
authors.forename: Alessandra Mirtes Marques Neves
authors.initials: AMMN
authors.lastname: Gonçalves
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Divinópolis, MG, Brazil.
authors.forename: Fabio Vieira Dos
authors.initials: FVD
authors.lastname: Santos
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Divinópolis, MG, Brazil.
authors.forename: Gustavo Henrique Ribeiro
authors.initials: GHR
authors.lastname: Viana
authors.affiliation: Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del Rei, Divinópolis, MG, Brazil.
authors.forename: Fernando de Pilla
authors.identifier: 0000-0002-2939-7780
authors.initials: FP
authors.lastname: Varotti
authors.affiliation: Serviço de Biologia Celular, Fundação Ezequiel Dias, Belo Horizonte, MG, Brazil.
authors.forename: Luciana Maria
authors.initials: LM
authors.lastname: Silva
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051927:CD24 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D018613:Microscopy, Confocal; D011714:Pyrans / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D011714:Pyrans; D011725:Pyridines; C023666:pyridine
keywords: 3-alkylpyridine alkaloid analogues; apoptosis; breast cancer; cancer stem cells; tumorspheres