Survivin is not induced by novel taxanes

Nima Sharifi, Jun Qi, Susan Bane, Shubhada Sharma, Rui Li, Robert Robey, William D. Figg, William L. Farrar, David G I Kingston

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Taxanes are a critical component of chemotherapy for breast, prostate, lung and other cancers. Initial or acquired tumor resistance to taxanes is therefore one of the most important issues in oncology. Survivin is a prosurvival gene whose expression is a poor prognostic feature. Survivin is induced acutely upon exposure to taxanes and coordinates resistance to taxane-mediated cell death, although the exact mechanism of taxane-mediated survivin induction is not clear. Here, we describe the synthesis of a series of novel taxanes, with modifications on the 7- or 10-position of the taxane backbone, as well as the side chain. We found that the novel taxanes with modifications at the 10-position have robust tubulin binding and tubulin polymerization activity. Gene expression profiling and quantitative PCR of cells treated with the 10-position conjugates reveals that the effect of treatment with a subset of these novel taxanes lacks a gene expression signature, including survivin induction, which is characteristically induced with paclitaxel treatment. Furthermore, we show that this gene expression signature is not due to differences in G2/M arrest. Cell sensitivity studies suggest that the inability to induce survivin is associated with increased drug cytotoxicity and apoptosis. This work suggests that taxanes that effectively bind tubulin need not invariably induce survivin as a mechanism of drug resistance.

Original languageEnglish (US)
Pages (from-to)2216-2223
Number of pages8
JournalMolecular Pharmaceutics
Volume7
Issue number6
DOIs
StatePublished - Dec 6 2010

Fingerprint

Taxoids
Tubulin
Transcriptome
Gene Expression Profiling
Paclitaxel
Drug Resistance
Polymerization
Prostate
Lung Neoplasms
Breast
Cell Death
Apoptosis
Gene Expression
Drug Therapy
Polymerase Chain Reaction
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

Cite this

Sharifi, N., Qi, J., Bane, S., Sharma, S., Li, R., Robey, R., ... Kingston, D. G. I. (2010). Survivin is not induced by novel taxanes. Molecular Pharmaceutics, 7(6), 2216-2223. https://doi.org/10.1021/mp100211k

Survivin is not induced by novel taxanes. / Sharifi, Nima; Qi, Jun; Bane, Susan; Sharma, Shubhada; Li, Rui; Robey, Robert; Figg, William D.; Farrar, William L.; Kingston, David G I.

In: Molecular Pharmaceutics, Vol. 7, No. 6, 06.12.2010, p. 2216-2223.

Research output: Contribution to journalArticle

Sharifi, N, Qi, J, Bane, S, Sharma, S, Li, R, Robey, R, Figg, WD, Farrar, WL & Kingston, DGI 2010, 'Survivin is not induced by novel taxanes', Molecular Pharmaceutics, vol. 7, no. 6, pp. 2216-2223. https://doi.org/10.1021/mp100211k
Sharifi N, Qi J, Bane S, Sharma S, Li R, Robey R et al. Survivin is not induced by novel taxanes. Molecular Pharmaceutics. 2010 Dec 6;7(6):2216-2223. https://doi.org/10.1021/mp100211k
Sharifi, Nima ; Qi, Jun ; Bane, Susan ; Sharma, Shubhada ; Li, Rui ; Robey, Robert ; Figg, William D. ; Farrar, William L. ; Kingston, David G I. / Survivin is not induced by novel taxanes. In: Molecular Pharmaceutics. 2010 ; Vol. 7, No. 6. pp. 2216-2223.
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