Author | Ayoub, Ahmed Taha | |
Author | Abou El-Magd, Rabab M. | |
Author | Xiao, Jack | |
Author | Lewis, Cody Wayne | |
Author | Tilli, Tatiana Martins | |
Author | Arakawa, Kenji | |
Author | Nindita, Yosi | |
Author | Chan, Gordon | |
Author | Sun, Luxin | |
Author | Glover, Mark | |
Author | Klobukowski, Mariusz | |
Author | Tuszynski, Jack | |
Access date | 2024-11-02T03:16:46Z | |
Available date | 2024-11-02T03:16:46Z | |
Document date | 2016 | |
Citation | AYOUB, Ahmed Taha; AYOUB, Ahmed Taha; ABOU EL-MAGD, Rabab M.; ABOU EL-MAGD, Rabab M.; XIAO, Jack; LEWIS, Cody Wayne; LEWIS, Cody Wayne; TILLI, Tatiana Martins; ARAKAWA, Kenji; NINDITA, Yosi; CHAN, Gordon; CHAN, Gordon; SUN, Luxin; GLOVER, Mark; KLOBUKOWSKI, Mariusz; TUSZYNSKI, Jack. Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism. Journal of Medicinal Chemistry, United States, v. 59, n. 20, p. 9532-9532, 2016. DOI: 10.1021/ACS.JMEDCHEM.6B01264. | en_US |
ISSN | 0022-2623 | en_US |
URI | https://www.arca.fiocruz.br/handle/icict/66861 | |
Abstract in Portuguese | Os antibióticos do grupo lankacidina mostram forte atividade antimicrobiana contra várias bactérias Gram-positivas. Além disso, eles demonstraram ter considerável atividade antitumoral contra certos modelos de linhagem celular. Por décadas, a atividade antitumoral da lankacidina foi associada ao mecanismo de sua ação antimicrobiana, que é a interferência na formação de ligações peptídicas durante a síntese de proteínas. Isso, no entanto, nunca foi confirmado experimentalmente. Devido à semelhança significativa com acertos semelhantes ao paclitaxel em um estudo anterior de triagem virtual computacional, sugerimos que o efeito citotóxico da lankacidina é devido a uma ação semelhante ao paclitaxel. Neste estudo, testamos essa hipótese computacionalmente e experimentalmente e confirmamos que a lankacidina é um estabilizador de microtúbulos que melhora a montagem da tubulina e desloca os taxoides de seu sítio de ligação. Este estudo serve como um ponto de partida para a otimização de derivados da lankacidina para melhores atividades antitumorais. Ele também destaca o poder das previsões computacionais e sua ajuda na orientação de experimentos e na formulação de hipóteses rigorosas. | en_US |
Language | eng | en_US |
Publisher | American Chemical Society | en_US |
Rights | restricted access | en_US |
MeSH | Animals | en_US |
MeSH | Anti-Bacterial Agents | en_US |
MeSH | Antineoplastic Agents | en_US |
MeSH | Binding Sites | en_US |
MeSH | Brain | en_US |
MeSH | Cell Survival | en_US |
MeSH | Dose-Response Relationship, Drug | en_US |
MeSH | HeLa Cells | en_US |
MeSH | Humans | en_US |
MeSH | Macrolides | en_US |
MeSH | Microtubules | en_US |
MeSH | Molecular Conformation | en_US |
MeSH | Molecular Dynamics Simulation | en_US |
MeSH | Paclitaxel | en_US |
MeSH | Structure-Activity Relationship | en_US |
MeSH | Swine | en_US |
MeSH | Tubulin | en_US |
MeSH | Tumor Cells, Cultured | en_US |
Subject in Portuguese | Atividade antitumoral | en_US |
Subject in Portuguese | Antibióticos do grupo lankacidin | en_US |
Subject in Portuguese | Estabilização de microtúbulos | en_US |
Subject in Portuguese | Mecanismo semelhante ao paclitaxel | en_US |
Title | Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism | en_US |
Type | Article | en_US |
DOI | 10.1021/ACS.JMEDCHEM.6B01264 | |
Abstract | Lankacidin group antibiotics show strong antimicrobial activity against various Gram-positive bacteria. In addition, they were shown to have considerable antitumor activity against certain cell line models. For decades, the antitumor activity of lankacidin was associated with the mechanism of its antimicrobial action, which is interference with peptide bond formation during protein synthesis. This, however, was never confirmed experimentally. Due to significant similarity to paclitaxel-like hits in a previous computational virtual screening study, we suggested that the cytotoxic effect of lankacidin is due to a paclitaxel-like action. In this study, we tested this hypothesis computationally and experimentally and confirmed that lankacidin is a microtubule stabilizer that enhances tubulin assembly and displaces taxoids from their binding site. This study serves as a starting point for optimization of lankacidin derivatives for better antitumor activities. It also highlights the power of computational predictions and their aid in guiding experiments and formulating rigorous hypotheses. | en_US |
Affilliation | Department of Chemistry, University of Alberta, Edmonton, Canada / Medicinal Chemistry Department, Heliopolis University, Cairo, Egypt | en_US |
Affilliation | Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada / City for Scientific Research and Technology Applications, Alexandria, Egypt | en_US |
Affilliation | Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Canada | en_US |
Affilliation | Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada / Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Canada | en_US |
Affilliation | National Institute of Science and Technology for Innovation in Neglected Diseases, Rio de Janeiro, Brazil | en_US |
Affilliation | Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Hiroshima, Japan | en_US |
Affilliation | Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Hiroshima, Japan | en_US |
Affilliation | Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada / Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, Canada | en_US |
Affilliation | Department of Biochemistry, University of Alberta, Edmonton, Canada | en_US |
Affilliation | Department of Biochemistry, University of Alberta, Edmonton, Canada | en_US |
Affilliation | Department of Chemistry, University of Alberta, Edmonton, Canada | en_US |
Affilliation | Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada | en_US |
Affilliation | Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas. Rio de Janeiro, RJ, Brasil. | en_US |
Subject | Antitumor Activity | en_US |
Subject | Lankacidin Group Antibiotics | en_US |
Subject | Microtubule Stabilization | en_US |
Subject | Paclitaxel-like Mechanism | en_US |
e-ISSN | 1520-4804 | |