Cellular effects of the microtubule-targeting agent peloruside A in hypoxia-conditioned colorectal carcinoma cells
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
28366502
DOI
10.1016/j.bbagen.2017.03.023
PII: S0304-4165(17)30124-1
Knihovny.cz E-resources
- Keywords
- Apoptosis, Hypoxia, Microtubule, Multi-drug resistance, Paclitaxel, Peloruside A,
- MeSH
- Apoptosis drug effects MeSH
- Bridged Bicyclo Compounds, Heterocyclic pharmacology MeSH
- HT29 Cells MeSH
- Cyclin B1 metabolism MeSH
- HCT116 Cells MeSH
- Cell Hypoxia * MeSH
- Cell Cycle Checkpoints drug effects MeSH
- Lactones pharmacology MeSH
- Humans MeSH
- Microtubules drug effects MeSH
- Paclitaxel pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents pharmacology MeSH
- Vincristine pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Bridged Bicyclo Compounds, Heterocyclic MeSH
- CCNB1 protein, human MeSH Browser
- Cyclin B1 MeSH
- Lactones MeSH
- Paclitaxel MeSH
- peloruside A MeSH Browser
- Antineoplastic Agents MeSH
- Vincristine MeSH
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. GENERAL SIGNIFICANCE: 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.
Biological Sciences Victoria University of Wellington Wellington New Zealand
Schools of Chemical and Physical Sciences Victoria University of Wellington Wellington New Zealand
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