title: Antitumor Activity of Lankacidin Group Antibiotics Is Due to Microtubule Stabilization via a Paclitaxel-like Mechanism.
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.
authors.affiliation: Department of Chemistry, University of Alberta , Edmonton, AB, T6G 2G2, Canada.|Medicinal Chemistry Department, Heliopolis University , Cairo 11777, Egypt.
authors.forename: Ahmed Taha
authors.initials: AT
authors.lastname: Ayoub
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta , Edmonton, AB, T6G 1Z2, Canada.|City for Scientific Research and Technology Applications , Alexandria, 21934 Egypt.
authors.forename: Rabab M
authors.initials: RM
authors.lastname: Abou El-Magd
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta , Edmonton, AB, T6G 1H9, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta , Edmonton, AB, T6G 1Z2, Canada.|Cancer Research Institute of Northern Alberta, University of Alberta , Edmonton, AB, T6G 2J7, Canada.
authors.forename: Cody Wayne
authors.initials: CW
authors.lastname: Lewis
authors.affiliation: National Institute of Science and Technology for Innovation in Neglected Diseases , Rio de Janeiro, 21040-361 Brazil.
authors.forename: Tatiana Martins
authors.initials: TM
authors.lastname: Tilli
authors.affiliation: Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University , Hiroshima 739-8530, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Arakawa
authors.affiliation: Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University , Hiroshima 739-8530, Japan.
authors.forename: Yosi
authors.initials: Y
authors.lastname: Nindita
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta , Edmonton, AB, T6G 1Z2, Canada.|Cancer Research Institute of Northern Alberta, University of Alberta , Edmonton, AB, T6G 2J7, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Biochemistry, University of Alberta , Edmonton, AB, T6G 2H7, Canada.
authors.forename: Luxin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, University of Alberta , Edmonton, AB, T6G 2H7, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Glover
authors.affiliation: Department of Chemistry, University of Alberta , Edmonton, AB, T6G 2G2, Canada.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Klobukowski
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta , Edmonton, AB, T6G 1Z2, Canada.
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D017239:Paclitaxel / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; C008250:lankacidins; D017239:Paclitaxel