Document Detail

Peloruside- and laulimalide-resistant human ovarian carcinoma cells have βI-tubulin mutations and altered expression of βII- and βIII-tubulin isotypes.
MedLine Citation:
PMID:  21653684     Owner:  NLM     Status:  MEDLINE    
Peloruside A and laulimalide are potent microtubule-stabilizing natural products with a mechanism of action similar to that of paclitaxel. However, the binding site of peloruside A and laulimalide on tubulin remains poorly understood. Drug resistance in anticancer treatment is a serious problem. We developed peloruside A- and laulimalide-resistant cell lines by selecting 1A9 human ovarian carcinoma cells that were able to grow in the presence of one of these agents. The 1A9-laulimalide resistant cells (L4) were 39-fold resistant to the selecting agent and 39-fold cross-resistant to peloruside A, whereas the 1A9-peloruside A resistant cells (R1) were 6-fold resistant to the selecting agent while they remained sensitive to laulimalide. Neither cell line showed resistance to paclitaxel or other drugs that bind to the taxoid site on β-tubulin nor was there resistance to microtubule-destabilizing drugs. The resistant cells exhibited impaired peloruside A/laulimalide-induced tubulin polymerization and impaired mitotic arrest. Tubulin mutations were found in the βI-tubulin isotype, R306H or R306C for L4 and A296T for R1 cells. This is the first cell-based evidence to support a β-tubulin-binding site for peloruside A and laulimalide. To determine whether the different resistance phenotypes of the cells were attributable to any other tubulin alterations, the β-tubulin isotype composition of the cells was examined. Increased expression of βII- and βIII-tubulin was observed in L4 cells only. These results provide insight into how alterations in tubulin lead to unique resistance profiles for two drugs, peloruside A and laulimalide, that have a similar mode of action.
Arun Kanakkanthara; Anja Wilmes; Aurora O'Brate; Daniel Escuin; Ariane Chan; Ada Gjyrezi; Janet Crawford; Pisana Rawson; Bronwyn Kivell; Peter T Northcote; Ernest Hamel; Paraskevi Giannakakou; John H Miller
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-06-08
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  10     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-10     Completed Date:  2011-12-19     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1419-29     Citation Subset:  IM    
Copyright Information:
©2011 AACR
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
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MeSH Terms
Antineoplastic Agents / metabolism,  pharmacology*
Bicyclo Compounds, Heterocyclic / metabolism,  pharmacology*
Binding Sites
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Lactones / metabolism,  pharmacology*
Macrolides / metabolism,  pharmacology*
Mutation / genetics*
Ovarian Neoplasms / genetics*,  metabolism,  pathology
Protein Binding
Protein Multimerization / drug effects
Tubulin / genetics*,  metabolism
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Bicyclo Compounds, Heterocyclic; 0/Lactones; 0/Macrolides; 0/Tubulin; 0/laulimalide; 0/peloruside A

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