title: Cellular effects of the microtubule-targeting agent peloruside A in hypoxia-conditioned colorectal carcinoma cells.
abstract: Hypoxia is a prominent feature of solid tumors, dramatically remodeling microtubule structures and cellular pathways and contributing to paclitaxel resistance. Peloruside A (PLA), a microtubule-targeting agent, has shown promising anti-tumor effects in preclinical studies. Although it has a similar mode of action to paclitaxel, it binds to a distinct site on β-tubulin that differs from the classical taxane site. In this study, we examined the unexplored effects of PLA in hypoxia-conditioned colorectal HCT116 cancer cells.
  
  
  
  Cytotoxicity of PLA was determined by cell proliferation assay. The effects of a pre-exposure to hypoxia on PLA-induced cell cycle alterations and apoptosis were examined by flow cytometry, time-lapse imaging, and western blot analysis of selected markers. The hypoxia effect on stabilization of microtubules by PLA was monitored by an intracellular tubulin polymerization assay.
  
  
  
  Our findings show that the cytotoxicity of PLA is not altered in hypoxia-conditioned cells compared to paclitaxel and vincristine. Furthermore, hypoxia does not alter PLA-induced microtubule stabilization nor the multinucleation of cells. PLA causes cyclin B1 and G2/M accumulation followed by apoptosis.
  
  
  
  The cellular and molecular effects of PLA have been determined in normoxic conditions, but there are no reports of PLA effects in hypoxic cells. Our findings reveal that hypoxia preconditioning does not alter the sensitivity of HCT116 to PLA.
  
  
  
  These data report on the cellular and molecular effects of PLA in hypoxia-conditioned cells for the first time, and will encourage further exploration of PLA as a promising anti-tumor agent.
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Řehulka
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
authors.forename: Narendran
authors.initials: N
authors.lastname: Annadurai
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
authors.forename: Ivo
authors.initials: I
authors.lastname: Frydrych
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
authors.forename: Pawel
authors.initials: P
authors.lastname: Znojek
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Džubák
authors.affiliation: Schools of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Peter
authors.initials: P
authors.lastname: Northcote
authors.affiliation: Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: John H
authors.initials: JH
authors.lastname: Miller
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic.
authors.forename: Marián
authors.initials: M
authors.lastname: Hajdúch
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900 Olomouc, Czech Republic. Electronic address: viswanath.das@upol.cz.
authors.forename: Viswanath
authors.initials: V
authors.lastname: Das
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C534699:CCNB1 protein, human; D056744:Cyclin B1; D007783:Lactones; C414085:peloruside A; D014750:Vincristine; D017239:Paclitaxel
keywords: Apoptosis; Hypoxia; Microtubule; Multi-drug resistance; Paclitaxel; Peloruside A